US8552215B2 - Method for producing optically active 2-hydroxy ester and novel intermediate compound - Google Patents
Method for producing optically active 2-hydroxy ester and novel intermediate compound Download PDFInfo
- Publication number
- US8552215B2 US8552215B2 US13/255,465 US201013255465A US8552215B2 US 8552215 B2 US8552215 B2 US 8552215B2 US 201013255465 A US201013255465 A US 201013255465A US 8552215 B2 US8552215 B2 US 8552215B2
- Authority
- US
- United States
- Prior art keywords
- carboxylic acid
- nmr
- hydroxy ester
- cdcl
- acid anhydride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related, expires
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 title claims description 32
- 239000002904 solvent Substances 0.000 claims abstract description 59
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims abstract description 41
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 39
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 19
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 116
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 claims description 15
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 11
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- YZMRCMTTYLBDPD-UHFFFAOYSA-N (2,2-diphenylacetyl) 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)C(=O)OC(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 YZMRCMTTYLBDPD-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000000962 organic group Chemical group 0.000 claims description 7
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- YGCWPCVAVSIFLO-LBPRGKRZSA-N (2r)-2-phenyl-1,2-dihydroimidazo[2,1-b][1,3]benzothiazole Chemical compound C1([C@@H]2CN3C4=CC=CC=C4SC3=N2)=CC=CC=C1 YGCWPCVAVSIFLO-LBPRGKRZSA-N 0.000 abstract description 12
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 abstract description 2
- 229960001614 levamisole Drugs 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 180
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 156
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 238000006243 chemical reaction Methods 0.000 description 83
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 59
- 238000005160 1H NMR spectroscopy Methods 0.000 description 49
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 43
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- 238000004896 high resolution mass spectrometry Methods 0.000 description 42
- 239000012043 crude product Substances 0.000 description 35
- 239000000203 mixture Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 239000007788 liquid Substances 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 26
- 239000011734 sodium Substances 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000010410 layer Substances 0.000 description 22
- 230000000704 physical effect Effects 0.000 description 20
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 0 *NC(=O)CC.*NC(=O)CCC.*NCCCCC.*OC(C)C.*OC1=CC=C(CC)C=C1.*OCC.*SCC.CC.CC(C)C.CC1=CC=CC=C1.CCC(C)C.CCC(C)C.CCC1=CC=CC=C1.CCC1=CN=CN1.CCC1=CNC2=C1C=CC=C2.CCCSC Chemical compound *NC(=O)CC.*NC(=O)CCC.*NCCCCC.*OC(C)C.*OC1=CC=C(CC)C=C1.*OCC.*SCC.CC.CC(C)C.CC1=CC=CC=C1.CCC(C)C.CCC(C)C.CCC1=CC=CC=C1.CCC1=CN=CN1.CCC1=CNC2=C1C=CC=C2.CCCSC 0.000 description 14
- 229910004161 SiNa Inorganic materials 0.000 description 14
- 238000000605 extraction Methods 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000000926 separation method Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 150000005690 diesters Chemical class 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- ZYTLPUIDJRKAAM-UHFFFAOYSA-N benzyl 2-hydroxypropanoate Chemical compound CC(O)C(=O)OCC1=CC=CC=C1 ZYTLPUIDJRKAAM-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- -1 tri-substituted benzoic acid Chemical class 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 5
- XHLPRIJMQZUNTK-UHFFFAOYSA-N 2-Hydroxy-24-keto-octacosanolide Chemical compound OC1CCCCCCCCCCCCCCCCCCCCCC(=O)CCCCOC1=O XHLPRIJMQZUNTK-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001414 amino alcohols Chemical class 0.000 description 4
- ZYTLPUIDJRKAAM-QMMMGPOBSA-N benzyl (2s)-2-hydroxypropanoate Chemical compound C[C@H](O)C(=O)OCC1=CC=CC=C1 ZYTLPUIDJRKAAM-QMMMGPOBSA-N 0.000 description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- AVLRVLFXKJPNTG-UHFFFAOYSA-N (1-phenylcyclopentanecarbonyl) 1-phenylcyclopentane-1-carboxylate Chemical compound C1CCCC1(C=1C=CC=CC=1)C(=O)OC(=O)C1(C=2C=CC=CC=2)CCCC1 AVLRVLFXKJPNTG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- MTYYGTVXQJGGOF-BCPVCJPBSA-N C[C@@H]1CN2C(=N1)SC1=C2C=CC=C1.C[C@@H]1CN2CCSC2=N1.C[C@H]1CN2C(=N1)SC1=C2C=CC=C1.C[C@H]1CN2CCSC2=N1 Chemical compound C[C@@H]1CN2C(=N1)SC1=C2C=CC=C1.C[C@@H]1CN2CCSC2=N1.C[C@H]1CN2C(=N1)SC1=C2C=CC=C1.C[C@H]1CN2CCSC2=N1 MTYYGTVXQJGGOF-BCPVCJPBSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- FLAKUBHBXKBPNL-VWLOTQADSA-N benzyl (2s)-14-[tert-butyl(dimethyl)silyl]oxy-2-hydroxytetradecanoate Chemical compound CC(C)(C)[Si](C)(C)OCCCCCCCCCCCC[C@H](O)C(=O)OCC1=CC=CC=C1 FLAKUBHBXKBPNL-VWLOTQADSA-N 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 description 3
- 239000000077 insect repellent Substances 0.000 description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 3
- YGMHIBLUWGDWKP-UHFFFAOYSA-N (4-methoxybenzoyl) 4-methoxybenzoate Chemical compound C1=CC(OC)=CC=C1C(=O)OC(=O)C1=CC=C(OC)C=C1 YGMHIBLUWGDWKP-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- ROWKJAVDOGWPAT-UHFFFAOYSA-N CC(=O)C(C)O Chemical compound CC(=O)C(C)O ROWKJAVDOGWPAT-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N CCC(C)C(C)=O Chemical compound CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- OTFJXLZYKSFMCP-JFINJBMXSA-N CCCCCC(C)C[C@@H](CO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)OCC1=CC=C(OC)C=C1 Chemical compound CCCCCC(C)C[C@@H](CO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)OCC1=CC=C(OC)C=C1 OTFJXLZYKSFMCP-JFINJBMXSA-N 0.000 description 2
- XNAWIUOJIHQAQB-SANMLTNESA-N CCC[C@@H](CO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)OCC1=CC=C(OC)C=C1 Chemical compound CCC[C@@H](CO[Si](C1=CC=CC=C1)(C1=CC=CC=C1)C(C)(C)C)OCC1=CC=C(OC)C=C1 XNAWIUOJIHQAQB-SANMLTNESA-N 0.000 description 2
- CRXNCCDFWRSOCY-VWLOTQADSA-N COC1=CC=C(CO[C@@H](CCO)CO[Si](C2=CC=CC=C2)(C2=CC=CC=C2)C(C)(C)C)C=C1 Chemical compound COC1=CC=C(CO[C@@H](CCO)CO[Si](C2=CC=CC=C2)(C2=CC=CC=C2)C(C)(C)C)C=C1 CRXNCCDFWRSOCY-VWLOTQADSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- GEXRXOSMLUFVEE-GOSISDBHSA-N benzyl (2R)-2-(2,2-diphenylacetyl)oxypropanoate Chemical compound O([C@H](C)C(=O)OCC=1C=CC=CC=1)C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 GEXRXOSMLUFVEE-GOSISDBHSA-N 0.000 description 2
- XANDRLFOMIFEFY-UHFFFAOYSA-N benzyl 2-hydroxy-3-methylbutanoate Chemical compound CC(C)C(O)C(=O)OCC1=CC=CC=C1 XANDRLFOMIFEFY-UHFFFAOYSA-N 0.000 description 2
- FDAMGWWGSJQBEY-UHFFFAOYSA-N benzyl 2-hydroxypentanoate Chemical compound CCCC(O)C(=O)OCC1=CC=CC=C1 FDAMGWWGSJQBEY-UHFFFAOYSA-N 0.000 description 2
- 239000008366 buffered solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 description 2
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
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- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- CRIRTQCGCHLRCW-CYBMUJFWSA-N methyl (2R)-2-(2,2-diphenylacetyl)oxypropanoate Chemical compound C=1C=CC=CC=1C(C(=O)O[C@H](C)C(=O)OC)C1=CC=CC=C1 CRIRTQCGCHLRCW-CYBMUJFWSA-N 0.000 description 1
- LPEKGGXMPWTOCB-VKHMYHEASA-N methyl (S)-lactate Chemical compound COC(=O)[C@H](C)O LPEKGGXMPWTOCB-VKHMYHEASA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- FPTRJFGAAHNWEZ-UHFFFAOYSA-N trifluoromethylbenzene Chemical compound FC(F)(F)C1=CC=CC=C1.FC(F)(F)C1=CC=CC=C1 FPTRJFGAAHNWEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a method for producing an optically active 2-hydroxy ester, and a novel intermediate compound. More particularly, the present invention relates to a method for producing an optically active 2-hydroxy ester by carrying out kinetic optical resolution using a racemic 2-hydroxy ester as a substrate, and a novel intermediate compound that can be produced by the method.
- Optically active 2-hydroxy esters are one of useful organic molecules that can be widely used as medical drugs, pesticides, flavors, food additives, chemical products, optical materials, and the like. Therefore, development of an asymmetric synthesis method for rapidly and conveniently supplying these compounds is a very important study subject.
- Nonpatent Document 1 a method for producing an optically active 2-hydroxy-2-phenylacetic acid by hydrolyzing an ester moiety of a racemic 2-hydroxy-2-phenylacetic acid methyl ester with an enzyme, and the like are disclosed.
- Nonpatent Document 1 the substrate in the production method of Nonpatent Document 1 is limited to one having a phenyl group bonded to position 2; therefore, the method involves a problem of poor generality of the substrate.
- this production method does not directly produce an optically active 2-hydroxy ester, and thus lacks convenience for use in producing an optically active 2-hydroxy ester.
- Example 10 of Patent Document 1 demonstrates that optically active benzyl 2-hydroxypropanoate is obtained by subjecting one enantiomer of racemic benzyl 2-hydroxypropanoate to selective esterification in a solvent containing benzotetramisole as an asymmetric catalyst, p-methoxybenzoic acid anhydride, and 3-phenylpropionic acid.
- a reaction velocity ratio s is as low as 12.
- a reaction velocity ratio s of no less than 25 is theoretically needed.
- a highly efficient production method has been desired which achieves a reaction velocity ratio s of greater than 25.
- the present invention was made in view of such conventional problems, and an object of the invention is to provide a method for highly efficiently producing an optically active 2-hydroxy ester by carrying out kinetic optical resolution of a racemic 2-hydroxy ester as a substrate.
- another object of the present invention is to provide a novel intermediate compound that can be produced by the method.
- a first aspect of the present invention provides a method for producing an optically active 2-hydroxy ester, the method including selectively esterifying one enantiomer of a racemic 2-hydroxy ester in a solvent containing a catalyst represented by any one of the following formulae (a) to (d), and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid, the carboxylic acid anhydride being an anhydride of a carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the ⁇ -position, provided that the solvent contains a carboxylic acid anhydride but does not contain a carboxylic acid, whereas the carboxylic acid has a tertiary carbon atom or a quaternary carbon atom in the ⁇ -position, provided that the solvent contains a carboxylic acid anhydride and a carboxylic acid,
- X represents any one of the following substituents:
- R represents a protecting group
- a second aspect of the present invention provides the method for producing an optically active 2-hydroxy ester according to the first aspect, wherein the one enantiomer of the racemic 2-hydroxy ester is selectively esterified in a solvent containing diphenylacetic acid anhydride as the carboxylic acid anhydride.
- a third aspect of the present invention provides the method for producing an optically active 2-hydroxy ester according to the first aspect, wherein the one enantiomer of the racemic 2-hydroxy ester is selectively esterified in a solvent containing pivalic acid anhydride as the carboxylic acid anhydride, and diphenylacetic acid as the carboxylic acid.
- a fourth aspect of the present invention provides the method for producing an optically active 2-hydroxy ester according to any one of the first to third aspects, wherein the solvent is a linear ether type solvent.
- a fifth aspect of the present invention provides an intermediate compound represented by the following formula (e):
- R e1 represents a monovalent organic group
- R e2 represents a hydrogen atom or a protecting group of a hydroxy group
- R ea represents a protecting group
- kinetic optical resolution carried out using a racemic 2-hydroxy ester as a substrate enables an optically active 2-hydroxy ester to be highly efficiently produced.
- a novel intermediate compound which can be produced with such a method may be provided.
- the method for producing an optically active 2-hydroxy ester according to the present invention includes selectively esterifying one enantiomer of a racemic 2-hydroxy ester in a solvent containing a particular catalyst, and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid. By thus selectively esterifying one enantiomer, an optically active 2-hydroxy ester can be obtained as another enantiomer not esterified.
- the racemic 2-hydroxy ester used in the production method of the present invention is represented by the following formula (f):
- R f1 and R f2 each independently represent a monovalent organic group.
- the monovalent organic group is not particularly limited, and an arbitrary monovalent organic group may be used. Specific examples include an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an arylalkyl group, and the like.
- the catalyst used in the production method of the present invention is represented by any one of the following formulae (a) to (d).
- X represents any one of the following substituents.
- R is a protecting group such as an alkyl group, an acyl group or a silyl group.
- the catalysts represented by the above formulae (a) to (d) are referred to as (+)-tetramisole and ( ⁇ )-tetramisole, respectively.
- the catalysts each represented by the above formulae (c) and (d), wherein X is a phenyl group are referred to as (+)-benzotetramisole, ( ⁇ )-benzotetramisole, respectively.
- These catalysts can be either obtained as a commercially available product, or synthesized using an amino acid having the substituent represented by X as a side chain.
- the carboxylic acid anhydride used in the production method of the present invention serves as an acylating agent.
- the carboxylic acid anhydride which may be used in this case is an anhydride of a carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the ⁇ -position.
- Specific examples of the anhydride include those of isobutyric acid, pivalic acid, cyclohexane carboxylic acid, diphenylacetic acid or dinaphthylacetic acid.
- the carboxylic acid anhydride used in the production method of the present invention serves as a dehydrative condensation agent.
- the carboxylic acid anhydride in this case is not particularly limited, those obtained from benzoic acid, benzoic acid having an electron donating group such as an alkyl group, an alkoxy group, an amino group or an alkoxyalkyl group bonded to a phenyl group, or a polysubstituted carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the ⁇ -position are preferred, and those obtained from benzoic acid, a mono-, di- or tri-substituted benzoic acid to which an alkyl group or an alkoxy group having 1 to 3 carbon atoms is bonded, diphenylacetic acid, pivalic acid, 1-phenyl-1-cyclopentanecarboxylic acid, 2-methyl-2-phenylpropionic acid, or
- diphenylacetic acid anhydride is particularly preferred, whereas pivalic acid anhydride is particularly preferred when the carboxylic acid is used in combination.
- the carboxylic acid used in the production method of the present invention has a tertiary carbon atom or a quaternary carbon atom in the ⁇ -position.
- the carboxylic acid include isobutyric acid, pivalic acid, cyclohexane carboxylic acid, diphenylacetic acid, dinaphthylacetic acid, and the like.
- diphenylacetic acid is particularly preferred in light of achievement of a high enantiomeric excess ee and a high reaction velocity ratio s.
- the solvent used in the production method of the present invention is exemplified by: halogenated alkyls such as dichloromethane and chloroform; linear ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether and cyclopentylmethyl ether; cyclic ethers such as tetrahydrofuran; aromatic compounds such as toluene, chlorobenzene, trifluoromethylbenzene (benzotrifluoride) and benzene; amides such as N,N-dimethylformamide and N-methylformamide; and the like.
- linear ether type solvents are particularly preferred.
- An optically active 2-hydroxy ester is produced by adding into a solvent a racemic 2-hydroxy ester, a catalyst, and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid. Furthermore, in order to neutralize an acid derived from a carboxylic acid anhydride produced as the reaction proceeds, addition of a base into the reaction system is preferred.
- the base is preferably an organic base not having nucleophilicity (trimethyl amine, triethylamine, diisopropyl ethylamine).
- the components may be added in any order into the solvent; however, sequentially adding the base, the catalyst, the racemic 2-hydroxy ester into a solvent containing a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid is preferred.
- each component to be added is not particularly limited, with respect to 1 equivalent of the racemic 2-hydroxy ester, 0.5 to 1.2 equivalents of the carboxylic acid anhydride, 0.5 to 0.75 equivalents of the carboxylic acid and 1.0 to 2.4 equivalents of the base, and 1 to 10% by mole of the catalyst may be used.
- the reaction temperature is preferably ⁇ 23 to 30° C., and the reaction time is preferably 10 min to 48 hrs.
- optically active 2-hydroxy ester After the reaction was thus allowed, general method for isolation and purification may be used to isolate an optically active 2-hydroxy ester. Specifically, the target substance is extracted by liquid separation with an organic solvent such as dichloromethane or diethyl ether, and the organic layer is then concentrated, followed by purification on chromatography of the concentrate. Accordingly, the optically active 2-hydroxy ester and a diester can be each isolated separately.
- an organic solvent such as dichloromethane or diethyl ether
- the intermediate compound according to the present invention is represented by the following formula (e):
- R e1 represents a monovalent organic group
- R e2 represents a hydrogen atom or a protecting group of a hydroxy group
- R e3 represents a protecting group such as a silyl group, a benzyl group, an acyl group or an acetal group.
- the monovalent organic group in R e1 is not particularly limited, and those illustrated above in connection with R f1 and the like may be used.
- the protecting group in R e2 is exemplified by an alkyl group, an acetyl group, a silyl group, and the like.
- the silyl group in R e3 is exemplified by a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, a t-butyldimethyl silyl (TBS) group, a triisopropyl silyl (TIPS) group, a tert-butyldiphenyl silyl (TBDPS) group, and the like.
- TMS trimethyl silyl
- TES triethyl silyl
- TBS t-butyldimethyl silyl
- TIPS triisopropyl silyl
- TDPS tert-butyldiphenyl silyl
- the intermediate compound is useful in producing for example, 2-hydroxy-24-oxooctacosanolide that is an insect repellent.
- One example of the method for producing 2-hydroxy-24-oxooctacosanolide is described later in Test Example 7.
- Benzyl (S)-14-(tert-butyldimethylsiloxy)-2-hydroxytetradecanoate obtained in Entry 26 of the aforementioned Test Example 3 is useful as, for example, an intermediate compound for producing 2-hydroxy-24-oxooctacosanolide that is an insect repellent. Accordingly, one example of the production method is shown in the following.
- the temperature of the reaction system was elevated to room temperature, followed by stirring the same for 1 hour.
- the reaction system was cooled to 0° C., and a saturated aqueous ammonium chloride solution was added thereto to stop the reaction.
- Celite was used to filtrate insoluble matter off. Liquid separation was carried out, and extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product.
- the reaction system was confirmed to be weekly acidic with a pH test paper, and stirred for 8.5 hrs.
- the temperature of the reaction system was elevated to room temperature, and water (5.9 mL) was added thereto. Thereafter, the reaction system was cooled to 0° C., and thereto was added a 6% aqueous sodium sulfite solution to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product of a compound L (599 mg, quant.) represented by the following formula. Thus obtained crude product was used in the next step without subjecting to purification.
- optically active hydroxy ester obtained according to the production method of the present invention is useful also in producing an optically active amino alcohol.
- One example of the method for producing an optically active amino alcohol is shown below.
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Abstract
Disclosed is a method for producing an optically active 2-hydroxy ester, comprising selectively esterifying one enantiomer of a racemic 2-hydroxy ester in a solvent containing a catalyst such as tetramisole or benzotetramisole, and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid. In particular, in the case where the solvent contains a carboxylic acid anhydride, but does not contain a carboxylic acid, as the carboxylic acid anhydride, a carboxylic acid anhydride containing a tertiary or quaternary carbon atom in the a-position is used. On the other hand, in the case where the solvent contains a carboxylic acid anhydride and a carboxylic acid, as the carboxylic acid, a carboxylic acid containing a tertiary or quaternary carbon atom in the a-position is used.
Description
This application is the National Stage of International Application No. PCT/JP2010/053789, filed Mar. 8, 2010, which claims the benefit of Japanese Application Nos. 2009-059850, filed Mar. 12, 2009, and 2009-244060, filed Oct. 23, 2009, the entire contents of all of which are incorporated by reference herein.
The present invention relates to a method for producing an optically active 2-hydroxy ester, and a novel intermediate compound. More particularly, the present invention relates to a method for producing an optically active 2-hydroxy ester by carrying out kinetic optical resolution using a racemic 2-hydroxy ester as a substrate, and a novel intermediate compound that can be produced by the method.
Optically active 2-hydroxy esters are one of useful organic molecules that can be widely used as medical drugs, pesticides, flavors, food additives, chemical products, optical materials, and the like. Therefore, development of an asymmetric synthesis method for rapidly and conveniently supplying these compounds is a very important study subject.
So far, a method for conveniently producing an optically active 2-hydroxy ester has been hardly reported. With respect to similar techniques, a method for producing an optically active 2-hydroxycarboxylic acid from a racemic 2-hydroxy ester has been reported in Nonpatent Document 1. In this Nonpatent Document 1, a method for producing an optically active 2-hydroxy-2-phenylacetic acid by hydrolyzing an ester moiety of a racemic 2-hydroxy-2-phenylacetic acid methyl ester with an enzyme, and the like are disclosed.
However, the substrate in the production method of Nonpatent Document 1 is limited to one having a phenyl group bonded to position 2; therefore, the method involves a problem of poor generality of the substrate. In addition, this production method does not directly produce an optically active 2-hydroxy ester, and thus lacks convenience for use in producing an optically active 2-hydroxy ester.
- Patent Document 1: PCT International Publication No. 2008/140074
- Nonpatent Document 1: Adv. Synth. Catal., 2001, 343, p. 547-558
It would be very advantageous if an optically active 2-hydroxy ester could be obtained by carrying out kinetic optical resolution using a racemic 2-hydroxy ester as a substrate. As only one example in the prior art, Example 10 of Patent Document 1 demonstrates that optically active benzyl 2-hydroxypropanoate is obtained by subjecting one enantiomer of racemic benzyl 2-hydroxypropanoate to selective esterification in a solvent containing benzotetramisole as an asymmetric catalyst, p-methoxybenzoic acid anhydride, and 3-phenylpropionic acid.
However, according to the production method disclosed in Patent Document 1, a reaction velocity ratio s is as low as 12. In an attempt to obtain an optically active 2-hydroxy ester having an enantiomeric excess of 99% in a yield of no less than 40% by kinetic optical resolution using a racemic 2-hydroxy ester as a substrate, a reaction velocity ratio s of no less than 25 is theoretically needed. Thus, a highly efficient production method has been desired which achieves a reaction velocity ratio s of greater than 25.
The present invention was made in view of such conventional problems, and an object of the invention is to provide a method for highly efficiently producing an optically active 2-hydroxy ester by carrying out kinetic optical resolution of a racemic 2-hydroxy ester as a substrate. In addition, another object of the present invention is to provide a novel intermediate compound that can be produced by the method.
The present inventors thoroughly investigated in order to solve the foregoing problems. Consequently, it was found that the aforementioned problems could be solved by using a particular carboxylic acid anhydride or carboxylic acid when one enantiomer of a racemic 2-hydroxy ester is selectively esterified in a solvent containing a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid. Accordingly, the present invention was completed. More specifically, aspects of the present invention are as in the following.
A first aspect of the present invention provides a method for producing an optically active 2-hydroxy ester, the method including selectively esterifying one enantiomer of a racemic 2-hydroxy ester in a solvent containing a catalyst represented by any one of the following formulae (a) to (d), and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid, the carboxylic acid anhydride being an anhydride of a carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the α-position, provided that the solvent contains a carboxylic acid anhydride but does not contain a carboxylic acid, whereas the carboxylic acid has a tertiary carbon atom or a quaternary carbon atom in the α-position, provided that the solvent contains a carboxylic acid anhydride and a carboxylic acid,
in the formulae (a) to (d), X represents any one of the following substituents:
and R represents a protecting group.)
A second aspect of the present invention provides the method for producing an optically active 2-hydroxy ester according to the first aspect, wherein the one enantiomer of the racemic 2-hydroxy ester is selectively esterified in a solvent containing diphenylacetic acid anhydride as the carboxylic acid anhydride.
A third aspect of the present invention provides the method for producing an optically active 2-hydroxy ester according to the first aspect, wherein the one enantiomer of the racemic 2-hydroxy ester is selectively esterified in a solvent containing pivalic acid anhydride as the carboxylic acid anhydride, and diphenylacetic acid as the carboxylic acid.
A fourth aspect of the present invention provides the method for producing an optically active 2-hydroxy ester according to any one of the first to third aspects, wherein the solvent is a linear ether type solvent.
A fifth aspect of the present invention provides an intermediate compound represented by the following formula (e):
in the formula (e), Re1 represents a monovalent organic group, Re2 represents a hydrogen atom or a protecting group of a hydroxy group, and Rea represents a protecting group.
According to the present invention, kinetic optical resolution carried out using a racemic 2-hydroxy ester as a substrate enables an optically active 2-hydroxy ester to be highly efficiently produced. In addition, a novel intermediate compound which can be produced with such a method may be provided.
Method for Producing Optically Active 2-Hydroxy Ester
The method for producing an optically active 2-hydroxy ester according to the present invention includes selectively esterifying one enantiomer of a racemic 2-hydroxy ester in a solvent containing a particular catalyst, and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid. By thus selectively esterifying one enantiomer, an optically active 2-hydroxy ester can be obtained as another enantiomer not esterified.
[Racemic 2-Hydroxy Ester]
The racemic 2-hydroxy ester used in the production method of the present invention is represented by the following formula (f):
In the above formula (f), Rf1 and Rf2 each independently represent a monovalent organic group. The monovalent organic group is not particularly limited, and an arbitrary monovalent organic group may be used. Specific examples include an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an arylalkyl group, and the like.
[Catalyst]
The catalyst used in the production method of the present invention is represented by any one of the following formulae (a) to (d).
In the above formulae (a) to (d), X represents any one of the following substituents. R is a protecting group such as an alkyl group, an acyl group or a silyl group.
Of the catalysts represented by the above formulae (a) to (d), the catalysts each represented by the above formulae (a) and (b), wherein X is a phenyl group, are referred to as (+)-tetramisole and (−)-tetramisole, respectively. The catalysts each represented by the above formulae (c) and (d), wherein X is a phenyl group, are referred to as (+)-benzotetramisole, (−)-benzotetramisole, respectively. These catalysts can be either obtained as a commercially available product, or synthesized using an amino acid having the substituent represented by X as a side chain.
[Carboxylic Acid Anhydride]
When the carboxylic acid described later is not used in combination, the carboxylic acid anhydride used in the production method of the present invention serves as an acylating agent. The carboxylic acid anhydride which may be used in this case is an anhydride of a carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the α-position. Specific examples of the anhydride include those of isobutyric acid, pivalic acid, cyclohexane carboxylic acid, diphenylacetic acid or dinaphthylacetic acid.
On the other hand, when the carboxylic acid described later is used in combination, the carboxylic acid anhydride used in the production method of the present invention serves as a dehydrative condensation agent. Although the carboxylic acid anhydride in this case is not particularly limited, those obtained from benzoic acid, benzoic acid having an electron donating group such as an alkyl group, an alkoxy group, an amino group or an alkoxyalkyl group bonded to a phenyl group, or a polysubstituted carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the α-position are preferred, and those obtained from benzoic acid, a mono-, di- or tri-substituted benzoic acid to which an alkyl group or an alkoxy group having 1 to 3 carbon atoms is bonded, diphenylacetic acid, pivalic acid, 1-phenyl-1-cyclopentanecarboxylic acid, 2-methyl-2-phenylpropionic acid, or 2,2-diphenyl propionic acid are more preferred.
Among these, when the carboxylic acid described later is not used in combination, diphenylacetic acid anhydride is particularly preferred, whereas pivalic acid anhydride is particularly preferred when the carboxylic acid is used in combination. By using these carboxylic acid anhydrides, the intended optically active 2-hydroxy ester can be obtained at a high yield and with a high reaction velocity ratio s.
[Carboxylic Acid]
The carboxylic acid used in the production method of the present invention has a tertiary carbon atom or a quaternary carbon atom in the α-position. Examples of the carboxylic acid include isobutyric acid, pivalic acid, cyclohexane carboxylic acid, diphenylacetic acid, dinaphthylacetic acid, and the like. Of these, diphenylacetic acid is particularly preferred in light of achievement of a high enantiomeric excess ee and a high reaction velocity ratio s.
[Solvent]
The solvent used in the production method of the present invention is exemplified by: halogenated alkyls such as dichloromethane and chloroform; linear ethers such as diethyl ether, diisopropyl ether, tert-butylmethyl ether and cyclopentylmethyl ether; cyclic ethers such as tetrahydrofuran; aromatic compounds such as toluene, chlorobenzene, trifluoromethylbenzene (benzotrifluoride) and benzene; amides such as N,N-dimethylformamide and N-methylformamide; and the like. Of these, in light of attaining high yields and high reaction velocity ratios s, linear ether type solvents are particularly preferred.
[Reaction Conditions, etc.]
An optically active 2-hydroxy ester is produced by adding into a solvent a racemic 2-hydroxy ester, a catalyst, and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid. Furthermore, in order to neutralize an acid derived from a carboxylic acid anhydride produced as the reaction proceeds, addition of a base into the reaction system is preferred. The base is preferably an organic base not having nucleophilicity (trimethyl amine, triethylamine, diisopropyl ethylamine).
The components may be added in any order into the solvent; however, sequentially adding the base, the catalyst, the racemic 2-hydroxy ester into a solvent containing a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid is preferred.
Although the amount of each component to be added is not particularly limited, with respect to 1 equivalent of the racemic 2-hydroxy ester, 0.5 to 1.2 equivalents of the carboxylic acid anhydride, 0.5 to 0.75 equivalents of the carboxylic acid and 1.0 to 2.4 equivalents of the base, and 1 to 10% by mole of the catalyst may be used.
The reaction temperature is preferably −23 to 30° C., and the reaction time is preferably 10 min to 48 hrs.
After the reaction was thus allowed, general method for isolation and purification may be used to isolate an optically active 2-hydroxy ester. Specifically, the target substance is extracted by liquid separation with an organic solvent such as dichloromethane or diethyl ether, and the organic layer is then concentrated, followed by purification on chromatography of the concentrate. Accordingly, the optically active 2-hydroxy ester and a diester can be each isolated separately.
Novel Intermediate Compound
The intermediate compound according to the present invention is represented by the following formula (e):
In the above formula (e): Re1 represents a monovalent organic group; Re2 represents a hydrogen atom or a protecting group of a hydroxy group; and Re3 represents a protecting group such as a silyl group, a benzyl group, an acyl group or an acetal group. The monovalent organic group in Re1 is not particularly limited, and those illustrated above in connection with Rf1 and the like may be used. Also, the protecting group in Re2 is exemplified by an alkyl group, an acetyl group, a silyl group, and the like. Moreover, the silyl group in Re3 is exemplified by a trimethyl silyl (TMS) group, a triethyl silyl (TES) group, a t-butyldimethyl silyl (TBS) group, a triisopropyl silyl (TIPS) group, a tert-butyldiphenyl silyl (TBDPS) group, and the like.
The intermediate compound is useful in producing for example, 2-hydroxy-24-oxooctacosanolide that is an insect repellent. One example of the method for producing 2-hydroxy-24-oxooctacosanolide is described later in Test Example 7.
Hereinafter, Examples of the present invention are explained, but the scope of the present invention is not limited to these Examples.
As shown in the above reaction scheme, to dichloromethane (0.2 M) containing 0.6 equivalents of p-methoxybenzoic acid anhydride (PMBA) and 0.5 equivalents of carboxylic acid were added 1.2 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole (BTM), and a solution containing 1 equivalent of racemic benzyl lactate in dichloromethane at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. It is to be noted that for Entries 6 and 7, the aqueous layer was extracted with dichloromethane. After the organic layer was mixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and unreacted optically active benzyl lactate. The results are shown in Table 1.
The enantiomeric excess ee was determined by an HPLC analytical method on a chiral column. Further, the reaction velocity ratio s was calculated based on the formula of: s=[ln(1−C) (ee of 1−product)]/[ln(1−C) (ee of 1+product)], according to a method of Kagan et al, (Top. Stereochem., 1988, 18, p. 249-330).
| TABLE 1 | ||||||
| No. | R1 | Yield [%] of 1a[a] | 1a /1c[b] | Yield [%] of 1b[a] | ee (1a;1b) [%] | s |
| 1 | Ph(CH2)2 | 33 | 86/14 | 54 | 80;42 | 14 |
| 2 | p-To1CH2 | 35 | 86/14 | 42 | 85;46 | 20 |
| 3 | i-Pr | 50 | 95/5 | 47 | 85;78 | 29 |
| 4 | c-Hex | 38 | 87/13 | 34 | 88;56 | 27 |
| 5 | Ph2CH | 35 | 80/20 | 48 | 95;62 | 70 |
| 6 | (α-Np)2CH | 8 | 84/16 | 86 | 94;6 | 35 |
| 7 | (β-Np)2CH | 31 | 89/11 | 52 | 95;51 | 63 |
| [a]Isolation yield | ||||||
| [b]Determined by 1H NMR | ||||||
As is seen from Table 1, when a carboxylic acid having a secondary carbon atom in the α-position like a carboxylic acid in which R1 is Ph(CH2)2 or p-TolCH2 was used, the reaction velocity ratio s was no greater than 20 in either case, which was not satisfactory (Entries 1 and 2). On the other hand, when a more bulky carboxylic acid having a tertiary carbon atom in the α-position was used, the reaction velocity ratio s was as high as no less than 27. Accordingly, optically active benzyl lactate was successfully obtained with high efficiency (Entries 3 to 7). In particular, when diphenylacetic acid was used as the carboxylic acid, all of the yield, the enantiomeric excess ee, and the reaction velocity ratio s were very high (Entry 5).
As shown in the above reaction scheme, to dichloromethane (0.2 M) containing 0.6 equivalents of carboxylic acid anhydride and 0.5 equivalents of diphenylacetic acid were added 1.2 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole (BTM), and a solution containing 1 equivalent of racemic benzyl lactate in dichloromethane at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. After the organic layer was mixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and unreacted optically active benzyl lactate. The results are shown in Table 2.
| TABLE 2 | ||||||
| No. | R2 | Yield [%] of 2a[a] | 2a /2c[b] | Yield [%] of 2b[a] | ee (2a;2b) [%] | s |
| 8 | Ph | 46 | 87/13 | 43 | 92;84 | 64 |
| 9 | 4-Me0C6H4 | 35 | 80/20 | 48 | 95;62 | 70 |
| 10 | t-Bu | 44 | 98/2 | 55 | 94;68 | 62 |
| 11 | PhMe2C | 27 | 98/2 | 43 | 95;75 | 92 |
| 12 | Ph2MoC | 37 | >99/<1 | 44 | 96;62 | 87 |
| 13 | Ph3C | 11 | >99/<1 | 75 | 97;12 | 72 |
| 14[c] | t-Bu | 44 | 98/2 | 55 | 97;82 | 146 |
| [a]Isolation yield | ||||||
| [b]Determined by 1H NMR | ||||||
| [c]Diethyl ether used in place of dichloromethane | ||||||
As is seen from Table 2, Test Example 2 in which diphenylacetic acid was used as the carboxylic acid exhibited a very high reaction velocity ratio s of no less than 62 for any of the carboxylic acid anhydrides of Entries 8 to 14 used. Also, when a bulky carboxylic acid anhydride such as pivalic acid anhydride was used, the amount of the by-product (compound 2c) was small (Entries 10 to 14), and particularly, when pivalic acid anhydride was used, a high yield was attained (Entries 10 and 14). Furthermore, when diethyl ether was used in place of dichloromethane, a prominently high reaction velocity ratio s was attained (Entry 14).
As shown in the above reaction scheme, to diethyl ether (0.2 M) containing 0.5 equivalents of diphenylacetic acid anhydride were added 0.5 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole (BTM), and a solution containing 1 equivalent of racemic 2-hydroxy ester in diethyl ether at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. After the organic layer was mixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and an unreacted optically active 2-hydroxy ester. The results are shown in Table 3.
In addition, in a similar manner to that described above except that diethyl ether containing 0.6 equivalents of pivalic acid anhydride and 0.5 equivalents of diphenylacetic acid was used in place of the diethyl ether containing 0.5 equivalents of diphenylacetic acid anhydride, a diester and an unreacted optically active 2-hydroxy ester were obtained. The results thus obtained are shown in Table 3 presented in parentheses.
| TABLE 3 | ||||
| Yield [%] [a] | ee [%] | |||
| No. | R3 | 3a; 3b | 3a; 3b | s |
| 15 | Me | 51; 49 | 97; 74 | 140 |
| (44; 55) | (97; 82) | (146) | ||
| 16 | Et | 48; 49 | 96; 86 | 152 |
| (46; 43) | (95; 94) | (126) | ||
| 17 | n-Pr | 45; 55 | 97; 84 | 149 |
| (50; 48) | (95; 97) | (171) | ||
| 18 | i-Pr | 40; 60 | 92; 66 | 46 |
| (46; 50) | (92; 73) | (53) | ||
| 19 | n-Bu | 45; 55 | 96; 86 | 125 |
| (47; 51) | (96; 88) | (128) | ||
| 20 | i-Bu | 46; 52 | 97; 87 | (167) |
| (45; 55) | (94; 97) | (140) | ||
| 21 | c-Hex | 38; 53 | 91; 63 | 42 |
| (43; 53) | (91; 75) | (47) | ||
| 22 | (CH2)2Ph | 47; 53 | 96; 86 | 140 |
| (48; 47) | (96; 95) | (202) | ||
| 23 | CH20TBS | 46; 54 | 94; 79 | 77 |
| (47; 50) | (93; 87) | (80) | ||
| 24 | (CH2)20TBS | 51; 49 | 93; 99 | 167 |
| (45; 52) | (96; 87) | (146) | ||
| 25 | (CH2)30TBS | 50; 43 | 95; 97 | 177 |
| (45; 59) | (97; 90) | (186) | ||
| 26 | (CH2)120TBS | 49; 49 | 95; 91 | 119 |
| (48; 48) | (96; 91) | (155) | ||
| [a] Isolation yield | ||||
As is seen from Table 3, all cases of Entries 15 to 26 exhibited prominently high enantiomeric excess ee and reaction velocity ratio s for any of the 2-hydroxy esters used. In addition, achieving a high enantiomeric excess ee and a high reaction velocity ratio s was enabled also in the case in which a silyl group was bonded to the end of R3 (Entries 23 to 26).
The production method and the physical properties of the optically active hydroxy esters and the diesters presented in Table 3 are shown below.
(Entry 17)
To diethyl ether (0.5 mL) containing diphenylacetic acid anhydride (45.2 mg, 0.111 mmol) were added diisopropyl ethylamine (19.4 μL, 0.111 mmol), (+)-benzotetramisole (2.8 mg, 0.0111 mmol), and a diethyl ether solution (0.6 mL) containing racemic benzyl 2-hydroxypentanoate (46.3 mg, 0.221 mmol) at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether five times. After the organic layer was mixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester (40.3 mg, 45%, 97% ee) and unreacted optically active benzyl 2-hydroxypentanoate (25.4 mg, 55%, 84% ee) as a colorless oily liquid (s=149).
HPLC (CHIRALPAK AS-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=15.0 min (98.6%), tR=19.8 min (1.4%);
IR (neat): 3479, 1737, 1456, 1136, 751, 698 cm−1;
1H NMR (CDCl3): δ7.41-7.32 (m, 5H, Ph), 5.21 (s, 2H, Bn), 4.23 (ddd, J=7.1, 5.0, 4.9 Hz, 1H, 2-H), 2.76 (d, J=5.0 Hz, 1H, OH), 1.82-1.73 (m, 1H, 3-H), 1.70-1.60 (m, 1H, 3-H), 1.53-1.34 (m, 2H, 4-H), 0.92 (t, J=7.5 Hz, 3H, 5-H);
13C NMR (CDCl3): δ174.8, 135.2, 128.63, 128.55, 128.4, 75.0, 67.3, 32.1, 18.8, 15.8;
HR MS: calcd for C12H16O3Na (M+Na+) 231.0992. found 231.0980.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=15.7 min (2.4%), tR=21.3 min (97.6%);
IR (neat): 1742, 1496, 1454, 747, 697 cm−1;
1H NMR (CDCl3): δ7.29-7.13 (m, 15H, Ph), 5.09 (d, J=12.0 Hz, 1H, Bn), 5.05 (d, J=12.0 Hz, 1H, Bn), 5.04 (s, 1H, 2′-H), 5.02 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 1.73-1.67 (m, 2H, 3-H), 1.21 (tq, J=7.5, 7.5 Hz, 2H, 4-H), 0.75 (t, J=7.5 Hz, 3H, 5-H);
13C NMR (CDCl3): δ172.1, 170.0, 138.35, 138.26, 135.3, 128.71, 128.71, 128.57, 128.55, 128.4, 128.3, 128.2, 127.3, 127.2, 72.8, 66.9, 56.8, 33.0, 18.3, 13.4;
HR MS: calcd for C26H26O4Na (M+Na+) 425.1723. found 475.1703.
(Entry 15)
HPLC (CHIRALCEL OD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=25.8 min (91.2%), tR=28.9 min (8.8%);
IR (neat): 3457, 1738, 1498, 1456, 1045, 752, 698 cm−1;
1H NMR (CDCl3): δ7.42-7.31 (m, 5H, Ph), 5.22 (s, 2H, Bn), 4.33 (dq, J=5.4, 6.9 Hz, 1H, 2-H), 2.81 (d, J=5.4 Hz, 1H, OH), 1.44 (d, J=6.9 Hz, 3H, 3-H);
13C NMR (CDCl3): δ175.5, 135.2, 128.6, 128.5, 128.2, 67.2, 66.8, 20.3;
HR MS: calcd for C10H12O3Na (M+Na+) 203.0679. found 203.0673.
HPLC (CHIRALCEL OJ-H, i-PrOH/hexane=2/3, flow rate=0.75 mL/min): tR=40.2 min (1.7%), tR=59.8 min (98.3%);
IR (neat): 1496, 1454, 747, 699 cm−1;
1H NMR (CDCl3): δ7.41-7.20 (m, 15H, Ph), 5.19 (q, J=7.2 Hz, 1H, 2-H); 5.18 (d, J=12.0 Hz, 1H, Bn); 5.13 (d, J=12.0 Hz, 1H, Bn); 5.11 (s, 1H, 2′-H), 1.49 (d, J=7.2 Hz, 3H, 3-H);
13C NMR (CDCl3): δ171.9, 170.4, 138.3, 138.2, 135.2, 128.70, 128.66, 128.58, 128.56, 128.48, 128.3, 128.1, 127.3, 127.2, 69.3, 67.0, 56.6, 16.8;
HR MS: calcd for C24H22O4Na (M+Na+) 397.1410. found 397.1427.
(Entry 16)
HPLC (CHIRALPAK AS-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=15.6 min (96.7%), tR=19.7 min (3.3%);
IR (neat): 3477, 1737, 1498, 1456, 1061, 752, 698 cm−1;
1H NMR (CDCl3): δ7.40-7.32 (m, 5H, Ph), 5.24 (d, J=12.3 Hz, 1H, Bn), 5.20 (d, J=12.3 Hz, 1H, Bn), 4.20 (ddd, J=11.3, 7.3, 4.0 Hz, 1H, 2-H), 2.83 (d, J=5.5 Hz, 1H, OH), 1.86 (ddq, J=14.5, 4.0, 7.0 Hz, 1H, 3-H), 1.70 (ddq, J=14.5, 7.3, 7.5 Hz, 1H, 3-H), 0.95 (dd, J=7.5, 7.0 Hz, 3H, 4-H);
13C NMR (CDCl3): δ175.0, 135.2, 128.6, 128.5, 128.3, 71.4, 67.2, 27.4, 8.8;
HR MS: calcd for C11H14O3Na (M+Na+) 217.0835. found 217.0825.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=17.4 min (2.7%), tR=20.9 min (97.3%);
IR (neat): 1736, 1496, 1454, 746, 699 cm−1;
1H NMR (CDCl3): δ7.29-7.13 (m, 15H, Ph), 5.09 (d, J=12.0 Hz, 1H, Bn), 5.05 (d, J=12.0 Hz, 1H, Bn), 5.05 (s, 1H, 2′-H), 4.97 (dd, J=7.5, 5.0 Hz, 1H, 2-H), 1.85-1.71 (m, 2H, 3-H), 0.77 (t, J=7.5 Hz, 3H, 4-H);
13C NMR (CDCl3): δ172.1, 169.8, 138.36, 138.27, 135.26, 128.71, 128.71, 128.57, 128.55, 128.4, 128.3, 128.2, 127.3, 127.2, 74.0, 66.9, 56.8, 24.5, 9.4;
HR MS: calcd for C25H24O4Na (M+Na+) 411.1567. found 411.1559.
(Entry 18)
HPLC (CHIRALCEL AS-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=11.7 min (86.3%), tR=17.0 min (13.7%);
IR (neat): 3508, 1735, 1498, 1456, 1030, 751, 698 cm−1;
1H NMR (CDCl3): δ7.41-7.34 (m, 5H, Ph), 5.24 (d, J=12.3 Hz, 1H, Bn), 5.20 (d, J=12.3 Hz, 1H, Bn), 4.09 (dd, J=6.3, 3.5 Hz, 1H, 2-H), 2.71 (d, J=6.3 Hz, 1H, OH), 2.10 (dqq, J=3.5, 7.0, 7.0 Hz, 1H, 3-H), 1.01 (d, J=7.0 Hz, 3H, 4-H), 0.83 (d, J=7.0 Hz, 3H, 4-H);
13C NMR (CDCl3): δ175.3, 135.2, 128.6, 128.5, 128.3, 70.3, 67.2, 36.4, 18.0, 13.7;
HR MS: calcd for C12H16O3Na (M+Na+) 231.0992. found 231.0985.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=16.9 min (4.0%), tR=21.8 min (96.0%);
IR (neat): 1739, 1496, 1454, 745, 698 cm−1;
1H NMR (CDCl3): δ7.29-7.12 (m, 15H, Ph), 5.09 (d, J=12.3 Hz, 1H, Bn), 5.06 (s, 1H, 2′-H), 5.05 (d, J=12.3 Hz, 1H, Bn), 4.85 (d, J=4.5 Hz, 1H, 2-H), 2.11 (dqq, J=4.5, 7.0, 6.8 Hz, 1H, 3-H), 0.76 (d, J=7.0 Hz, 3H, 4-H), 0.75 (d, J=6.8 Hz, 3H, 4-H);
13C NMR (CDCl3): δ172.1, 169.3, 138.4, 138.3, 135.3, 128.8, 128.7, 128.6, 128.5, 128.4, 128.33, 128.29, 127.26, 127.16, 77.4, 66.9, 56.9, 30.2, 18.6, 17.0;
HR MS: calcd for C26H26O4Na (M+Na+) 425.1723. found 425.1732.
(Entry 19)
HPLC (CHIRALCEL AS-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=12.9 min (93.8%), tR=16.5 min (6.2%);
IR (neat): 3478, 1738, 1498, 1456, 1137, 751, 698 cm−1;
1H NMR (CDCl3): δ7.42-7.32 (m, 5H, Ph), 5.23 (d, J=12.3 Hz, 1H, Bn), 5.20 (d, J=12.3 Hz, 1H, Bn), 4.27-4.18 (m, 1H, 2-H), 2.87 (d, J=5.5 Hz, 1H, OH), 1.87-1.74 (m, 1H, 3-H), 1.72-1.60 (m, 1H, 3-H), 1.48-1.25 (m, 4H, 4-H, 5-H), 0.88 (t, J=7.0 Hz, 3H, 6-H);
13C NMR (CDCl3): δ175.2, 135.2, 128.6, 128.5, 128.3, 70.5, 67.2, 34.0, 26.7, 22.3, 13.8;
HR MS: calcd for C13H18O3Na (M+Na+) 245.1148. found 245.1155.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=19.7 min (2.2%), tR=30.1 min (97.8%);
IR (neat): 1739, 1496, 1455, 736, 699 cm−1;
1H NMR (CDCl3): δ7.32-7.16 (m, 15H, Ph), 5.12 (d, J=12.3 Hz, 1H, Bn), 5.08 (d, J=12.3 Hz, 1H, Bn), 5.07 (s, 1H, 2′-H), 5.04 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 1.82-1.73 (m, 2H, 3-H), 1.23-1.10 (m, 4H, 4-H, 5-H), 0.78-0.71 (m, 3H, 6-H);
13C NMR (CDCl3): δ172.1, 170.0, 138.3, 138.2, 135.3, 128.71, 128.71, 128.6, 128.5, 128.4, 128.3, 128.2, 127.3, 127.2, 72.9, 66.9, 56.8, 30.7, 27.0, 22.0, 13.7;
HR MS: calcd for C27H28O4Na (M+Na+) 439.1880. found 439.1886.
(Entry 20)
HPLC (CHIRALCEL AS-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=12.6 min (98.3%), tR=18.0 min (1.7%);
IR (neat): 3474, 1737, 1498, 1456, 1090, 749, 698 cm−1;
1H NMR (CDCl3): δ7.33-7.24 (m, 5H, Ph), 5.14 (d, J=12.0 Hz, 1H, Bn), 5.11 (d, J=12.0 Hz, 1H, Bn), 4.17 (ddd, J=8.5, 5.5, 5.0 Hz, 1H, 2-H), 2.64 (d, J=5.5 Hz, 1H, OH), 1.87-1.75 (m, 1H, 4-H), 1.55-1.46 (m, 2H, 3-H), 0.86 (d, J=7.0 Hz, 3H, 5-H), 0.85 (d, J=7.0 Hz, 3H, 5-H);
13C NMR (CDCl3): δ175.7, 135.2, 128.6, 128.5, 128.3, 69.1, 67.2, 43.4, 24.4, 23.2, 21.5;
HR MS: calcd for C13H18O3Na (M+Na+) 245.1148. found 245.1156.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=14.2 min (2.8%), tR=25.2 min (97.2%);
IR (neat): 1739, 1496, 1454, 739, 699 cm−1;
1H NMR (CDCl3): δ7.29-7.13 (m, 15H, Ph), 5.10-5.00 (m, 4H, 2-H, 2′-H, Bn), 1.69 (ddd, J=14.0, 9.8, 4.5 Hz, 1H, 3-H), 1.58-1.41 (m, 3H, 3-H, 4-H), 0.75 (d, J=7.0 Hz, 3H, 5-H), 0.71 (d, J=6.5 Hz, 3H, 5-H);
13C NMR (CDCl3): δ172.1, 170.3, 138.3, 138.2, 135.2, 128.71, 128.69, 128.57, 128.54, 128.4, 128.3, 128.2, 127.3, 127.2, 71.7, 67.0, 56.8, 39.5, 24.5, 22.8, 21.3;
HR MS: calcd for C27H28O4Na (M+Na+) 439.1880. found 439.1879.
(Entry 21)
HPLC (CHIRALCEL AS-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=13.6 min (87.5%), tR=20.3 min (12.5%);
IR (neat): 3504, 1735, 1498, 1452, 1114, 750, 697 cm−1;
1H NMR (CDCl3): δ7.41-7.32 (m, 5H, Ph), 5.24 (d, J=12.0 Hz, 1H, Bn), 5.21 (d, J=12.0 Hz, 1H, Bn), 4.06 (d, J=3.5 Hz, 1H, 2-H), 2.69 (br s, 1H, OH), 1.81-1.57 (m, 5H, c-Hex), 1.43-1.03 (m, 6H, c-Hex);
13C NMR (CDCl3): δ174.7, 135.2, 128.6, 128.5, 128.3, 74.8, 67.2, 42.0, 29.0, 26.23, 26.18, 25.94, 25.89;
HR MS: calcd for C15H20O3Na (M+Na+) 271.1305. found 271.1306.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=18.6 min (4.6%), tR=34.6 min (95.4%);
IR (neat): 1741, 1496, 1453, 747, 697 cm−1;
1H NMR (CDCl3): δ7.27-7.13 (m, 15H, Ph), 5.09 (d, J=12.5 Hz, 1H, Bn), 5.06 (d, J=12.5 Hz, 1H, Bn), 5.05 (s, 1H, 2′-H), 4.84 (d, J=5.0 Hz, 1H, 2-H), 1.85-1.74 (m, 1H, c-Hex), 1.63-1.37 (m, 6H, c-Hex), 1.10-0.80 (m, 4H, c-Hex);
13C NMR (CDCl3): δ172.1, 169.3, 138.4, 138.3, 135.3, 128.78, 128.76, 128.54, 128.51, 128.4, 128.3, 128.2, 127.3, 127.1, 77.1, 66.8, 56.9, 39.5, 28.8, 27.3, 25.9, 25.8, 25.7;
HR MS: calcd for C29H30O4Na (M+Na+) 465.2036. found 465.2031.
(Entry 22)
Mp: 58.9-59.6° C. (hexane);
HPLC (CHIRALCEL OD-H, i-PrOH/hexane=1/4, flow rate=0.5 mL/min): tR=13.9 min (97.3%), tR=19.1 min (2.7%);
IR (KBr): 3429, 1728, 1496, 1451, 1105, 752, 699 cm−1;
1H NMR (CDCl3): δ7.32-7.23 (m, 5H, Ph), 7.22-7.16 (m, 2H, Ph), 7.13-7.05 (m, 3H, Ph), 5.11 (d, J=12.0 Hz, 1H, Bn), 5.08 (d, J=12.0 Hz, 1H, Bn), 4.16 (ddd, J=7.5, 5.5, 4.0 Hz, 1H, 2-H), 2.78 (d, J=5.5 Hz, 1H, OH), 2.72-2.56 (m, 2H, 4-H), 2.10-2.00 (m, 1H, 3-H), 1.93-1.83 (m, 1H, 3-H);
13C NMR (CDCl3): δ175.0, 141.1, 135.1, 128.7, 128.6, 128.5, 128.39, 128.38, 126.0, 69.7, 67.4, 35.9, 30.9;
HR MS: calcd for C17H18O3Na (M+Na+) 293.1148. found 293.1158.
Mp: 75.3-76.0° C. (hexane);
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/9, flow rate=0.5 mL/min): tR=22.0 min (1.8%), tR=23.3 min (97.2%);
IR (KBr): 1734, 1496, 1455, 735, 697 cm−1;
1H NMR (CDCl3): δ7.36-7.09 (m, 18H, Ph), 6.93-6.88 (m, 2H, Ph), 5.12 (d, J=12.0 Hz, 1H, Bn), 5.11 (s, 1H, 2′-H), 5.07 (d, J=12.0 Hz, 1H, Bn), 5.01 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 2.54-2.42 (m, 2H, 4-H), 2.12-2.05 (m, 2H, 3-H);
13C NMR (CDCl3): δ171.9, 169.7, 140.1, 138.3, 138.2, 135.2, 128.77, 128.77, 128.66, 128.58, 128.48, 128.44, 128.41, 128.38, 128.3, 127.4, 127.3, 126.2, 72.1, 67.1, 56.8, 32.6, 31.0;
HR MS: calcd for C31H28O4Na (M+Na+) 487.1880. found 487.1903.
(Entry 23)
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=9.6 min (6.3%), tR=10.4 min (93.7%);
IR (neat): 3506, 1748, 1462, 1123, 735, 697 cm−1;
1H NMR (CDCl3): δ7.39-7.31 (m, 5H, Ph), 5.22 (s, 2H, Bn), 4.26 (dt, J=8.5, 3.0 Hz, 1H, 2-H), 3.96 (dd, J=10.3, 3.0 Hz, 1H, 3-H), 3.87 (dd, J=10.3, 3.0 Hz, 1H, 3-H), 3.07 (d, J=8.5 Hz, 1H, OH), 0.86 (s, 9H, TBS), 0.04 (s, 3H, TBS), 0.02 (s, 3H, TBS);
13C NMR (CDCl3): δ172.6, 135.3, 128.6, 128.4, 128.3, 72.0, 67.2, 65.0, 25.7, 18.2, −5.5, −5.6;
HR MS: calcd for C16H26O4SiNa (M+Na+) 333.1493. found 333.1504.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=11.2 min (96.5%), tR=19.8 min (3.5%);
IR (neat): 1743, 1496, 1455, 746, 698 cm−1;
1H NMR (CDCl3): δ7.36-7.20 (m, 15H, Ph), 5.23 (dd, J=5.0, 3.0 Hz, 1H, 2-H), 5.18 (d, J=12.0 Hz, 1H, Bn), 5.14 (d, J=12.0 Hz, 1H, Bn), 5.13 (s, 1H, 2′-H), 4.03 (dd, J=11.5, 5.0 Hz, 1H, 3-H), 3.91 (dd, J=11.5, 3.0 Hz, 1H, 3-H), 0.80 (s, 9H, TBS), −0.05 (s, 3H, TBS), −0.06 (s, 3H, TBS);
13C NMR (CDCl3): δ172.0, 167.8, 138.3, 138.1, 135.2, 128.8, 128.7, 128.6, 128.53, 128.46, 128.3, 128.2, 127.3, 127.2, 74.4, 67.1, 62.6, 56.8, 25.6, 18.1, −5.58, −5.58;
HR MS: calcd for C30H36O5SiNa (M+Na+) 527.2224. found 527.2245.
(Entry 24)
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=10.0 min (6.3%), tR=11.9 min (93.7%);
IR (neat): 3489, 1733, 1471, 1111, 735, 697 cm−1;
1H NMR (CDCl3): δ7.39-7.31 (m, 5H, Ph), 5.23 (d, J=12.3 Hz, 1H, Bn), 5.19 (d, J=12.3 Hz, 1H, Bn), 4.40 (ddd, J=7.6, 5.5, 4.0 Hz, 1H, 2-H), 3.84-3.76 (m, 2H, 4-H), 3.31 (d, J=5.5 Hz, 1H, OH), 2.07 (dddd, J=14.2, 7.0, 5.5, 4.0 Hz, 1H, 3-H), 1.89 (dddd, J=14.2, 7.6, 6.0, 5.0 Hz, 1H, 3-H), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS);
13C NMR (CDCl3): δ174.7, 135.4, 128.6, 128.4, 128.3, 69.0, 67.0, 59.9, 36.2, 25.9, 18.2, −5.5, −5.6;
HR MS: calcd for C17H28O4SiNa (M+Na+) 347.1649. found 347.1634.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=9.8 min (98.1%), tR=11.8 min (1.9%);
IR (neat): 1740, 1497, 1455, 747, 699 cm−1;
1H NMR (CDCl3): δ7.46-7.31 (m, 15H, Ph), 5.36 (dd, J=9.0, 4.0 Hz, 1H, 2-H), 5.28 (d, J=12.3 Hz, 1H, Bn), 5.23 (d, J=12.3 Hz, 1H, Bn), 5.21 (s, 1H, 2′-H), 3.67 (ddd, J=10.3, 6.0, 4.5 Hz, 1H, 4-H), 3.60 (ddd, J=10.3, 8.0, 5.0 Hz, 1H, 4-H), 2.18 (dddd, J=14.1, 8.0, 6.0, 4.0 Hz, 1H, 3-H), 2.08 (dddd, J=14.1, 9.0, 5.0, 4.5 Hz, 1H, 3-H), 0.93 (s, 9H, TBS), 0.05 (s, 3H, TBS), 0.03 (s, 3H, TBS);
13C NMR (CDCl3): δ171.8, 170.1, 138.4, 138.2, 135.3, 128.74, 128.71, 128.6, 128.5, 128.4, 128.3, 128.1, 127.3, 127.2, 69.8, 66.9, 58.2, 56.8, 34.0, 25.8, 18.2, −5.5, −5.6;
HR MS: calcd for C31H38O5SiNa (M+Na+) 541.2381. found 541.2391.
(Entry 25)
HPLC (CHIRALPAK AS-H, i-PrOH/hexane=1/100, flow rate=1.0 mL/min): tR=10.9 min (95.4%), tR=17.0 min (4.6%);
IR (neat): 3470, 1732, 1471, 1102, 776, 697 cm−1;
1H NMR (CDCl3): δ7.39-7.12 (m, 5H, Ph), 5.22 (d, J=12.5 Hz, 1H, Bn), 5.19 (d, J=12.5 Hz, 1H, Bn), 4.26 (dd, J=7.5, 4.0 Hz, 1H, 2-H), 3.67-3.59 (m, 2H, 5-H), 1.96-1.88 (m, 1H, 3-H), 1.80-1.55 (m, 4H, 3-H, 4-H, OH), 0.88 (s, 9H, TBS), 0.04 (s, 6H, TBS);
13C NMR (CDCl3): δ174.9, 135.3, 128.6, 128.5, 128.2, 70.4, 67.1, 62.8, 31.4, 28.2, 25.9, 18.3, −5.41;
HR MS: calcd for C18H33O4SiNa (M+Na+) 361.1806. found 361.1822.
HPLC (CHIRALPAK IC, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=8.4 min (1.7%), tR=9.5 min (98.3%);
IR (neat): 1741, 1496, 1455, 836, 698 cm−1;
1H NMR (CDCl3): δ7.35-7.20 (m, 15H, Ph), 5.16 (d, J=12.5 Hz, 1H, Bn), 5.14 (d, J=12.5 Hz, 1H, Bn), 5.11 (s, 1H, 2′-H), 5.11 (dd, J=8.5, 5.0 Hz, 1H, 2-H), 3.51 (dd, J=6.0, 6.0 Hz, 2H, 5-H), 1.97-1.81 (m, 2H, 3-H), 1.50-1.41 (m, 2H, 4-H), 0.85 (s, 9H, TBS), −0.02 (s, 6H, TBS);
13C NMR (CDCl3): δ172.0, 170.0, 138.3, 138.2, 135.2, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, 127.3, 127.2, 72.8, 66.9, 62.0, 56.8, 28.0, 27.7, 25.9, 18.2, −5.40;
HR MS: calcd for C32H40O5SiNa (M+Na+) 555.2537. found 555.2559.
(Entry 26)
HPLC (CHIRALPAK IC, i-PrOH/hexane=1/50, flow rate=0.5 mL/min): tR=20.7 min (4.6%), tR=22.9 min (95.4%);
IR (neat): 3472, 1736, 1462, 775, 697 cm−1;
1H NMR (CDCl3): δ7.39-7.34 (m, 5H, Ph), 5.23 (d, J=12.0 Hz, 1H, Bn), 5.19 (d, J=12.0 Hz, 1H, Bn), 4.22 (dd, J=7.0, 4.5 Hz, 1H, 2-H), 3.60 (t, J=6.5 Hz, 2H, 14-H), 2.75 (br s, 1H, OH), 1.83-1.75 (m, 1H, 3-H), 1.69-1.60 (m, 1H, 3-H), 1.54-1.20 (m, 20H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, 13-H), 0.90 (s, 9H, TBS), 0.05 (s, 6H, TBS);
13C NMR (CDCl3): δ175.3, 135.2, 128.6, 128.5, 128.3, 70.5, 67.2, 63.3, 34.40, 34.38, 32.9, 29.62, 29.58, 29.56, 29.50, 29.4, 29.3, 26.0, 25.8, 24.6, 18.4, −5.27;
HR MS: calcd for C27H48O4SiNa (M+Na+) 487.3214. found 487.3230.
HPLC (CHIRALPAK AD-H, i-PrOH/hexane=1/100, flow rate=1.0 mL/min): tR=11.2 min (98.0%), tR=16.4 min (2.0%);
IR (neat): 1742, 1496, 1455, 836, 698 cm−1;
1H NMR (CDCl3): δ7.24-7.10 (m, 15H, Ph), 5.05 (d, J=12.3 Hz, 1H, Bn), 5.01 (d, J=12.3 Hz, 1H, Bn), 5.00 (s, 1H, 2′-H), 4.97 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 3.49 (t, J=6.5 Hz, 2H, 14-H), 1.71 (ddt, J=15.5, 7.0, 10.0 Hz, 1H, 3-H), 1.69 (ddt, J=15.5, 6.0, 9.0 Hz, 1H, 3-H), 1.40 (tt, J=7.0, 7.0 Hz, 2H, 13-H), 1.24-0.90 (m, 18H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H), 0.79 (s, 9H, TBS), −0.06 (s, 6H, TBS);
13C NMR (CDCl3): δ172.1, 170.0, 138.3, 138.2, 135.3, 128.71, 128.70, 128.6, 128.5, 128.4, 128.3, 128.2, 127.3, 127.2, 72.9, 66.9, 63.3, 56.8, 32.9, 31.0, 29.62, 29.56, 29.55, 29.43, 29.39, 29.26, 28.9, 26.0, 25.8, 24.9, 18.4, −5.27;
HR MS: calcd for C41H58O5SiNa (M+Na+) 681.3946. found 681.3965.
As shown in the above reaction scheme, to a solution containing 0.50 equivalents of diphenylacetic acid and 0.60 equivalents of 1-phenyl-1-cyclopentanecarboxylic acid anhydride in dichloromethane were sequentially added 1.2 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole ((+)-BTM), and the racemic 2-hydroxy ester at room temperature. This reaction mixture was then allowed to react at room temperature for 12 hrs, whereby a corresponding optically active ester and an unreacted 2-hydroxy ester were obtained. The results are shown in Table 4.
| TABLE 4 | ||||||
| Yield [%] [a] | ee [%] | |||||
| No. | R 4 | 4a; 4b | 4a; 4b | s | ||
| 27 | Me | 33; 58 | 97; 50 | 107 | ||
| 28 | Et | 31; 49 | 94; 52 | 58 | ||
| [a] Isolation yield | ||||||
As is seen from Table 4, also when 1-phenyl-1-cyclopentanecarboxylic acid anhydride and diphenylacetic acid were used in combination in place of diphenylacetic acid anhydride, prominently high enantiomeric excess ee and reaction velocity ratio s were attained (Entries 27 and 28).
The production method and the physical properties of the optically active hydroxy esters and the diesters presented in Table 4 are shown below.
(Entry 27)
To a solution containing 1-phenyl-1-cyclopentanecarboxylic acid anhydride (48.3 mg, 0.133 mmol) and diphenylacetic acid (23.6 mg, 0.111 mmol) in dichloromethane was added diisopropyl ethylamine (46.4 μL, 0.266 mmol) at room temperature. After this reaction mixture was stirred for 10 min, (+)-benzotetramisole (2.8 mg, 0.0111 mmol) and racemic benzyl lactate (35.7 μL, 0.222 mmol) were added thereto at room temperature. After this reaction mixture was stirred at room temperature for 12 hrs, saturated sodium bicarbonate water was added at room temperature to stop the reaction. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether five times. After the organic layer was mixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1), and a highly polar fraction was fractionated again on silica gel thin layer chromatography (developing solvent: benzene/ethyl acetate=9/1) to afford a corresponding diester (23.0 mg, 58%, 50% ee) and unreacted optically active benzyl lactate. Moreover, the poorly polar fraction was also fractionated on silica gel thin layer chromatography (developing solvent: hexane/diethyl ether=5/1) to afford a corresponding diester (7.6 mg, 33%, 97% ee) and unreacted optically active benzyl lactate.
[α]D 28=−10.0 (c 1.10, acetone);
HPLC (CHIRALPAK OD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=16.7 min (75.2%), tR=18.7 min (24.8%);
1H NMR (CDCl3): δ7.42-7.31 (m, 5H, Ph), 5.22 (s, 2H, Bn), 4.33 (ddd, J=13.4, 6.9, 5.4 Hz, 1H, 2-H), 2.81 (d, J=5.4 Hz, 1H, OH), 1.44 (d, J=6.9 Hz, 3H, 3-H).
[α]D 28=+34.6 (c 1.43, CHCl3);
HPLC (CHIRALPAK OD-H, i-PrOH/hexane=2/3, flow rate=1.0 mL/min): tR=30.6 min (1.5%), tR=46.3 min (98.5%);
1H NMR (CDCl3): δ7.41-7.20 (m, 15H, Ph), 5.24-5.13 (m, 3H, 2-H, Bn), 5.10 (s, 1H, 2′-H), 1.49 (d, J=7.2 Hz, 3H, 3-H).
As shown in the above reaction scheme, to diethyl ether (0.2 M) containing 0.6 equivalents of pivalic acid anhydride and 0.5 equivalents of diphenylacetic acid were added 1.2 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole (BTM), and a solution containing 1 equivalent of a racemic 2-hydroxy ester in diethyl ether at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. After the organic layers were admixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and unreacted optically active 2-hydroxy ester. The results are shown in Table 5.
| TABLE 5 | |||||
| Yield [%] [a] | cc [%] | ||||
| No. | R5 | R6 | 5a; 5b | 5a; 5b | s |
| 29 | Et | n-Pr | 47; 47 | 97; 89 | 217 |
| 30 | Me | Me | 47; 23 | 97; 68 | 119 |
| [a] Isolation yield | |||||
As is seen from Table 5, prominently high enantiomeric excess ee and reaction velocity ratio s were exhibited also when a material other than the benzyl ester was used (Entries 29 and 30).
The physical properties of the optically active hydroxy esters and the diesters in Table 5 are shown below.
(Entry 29)
1H NMR (CDCl3): δ4.19 (dq, J=14.0, 7.0 Hz, 1H, Eta), 4.18 (dq, J=14.0, 7.5 Hz, 1H, Eta), 2.96 (br d, J=3.5 Hz, 1H, OH), 1.75-1.65 (m, 1H, 3-H), 1.62-1.52 (m, 1H, 3-H), 1.48-1.30 (m, 2H, 4-H), 1.24 (dd, J=7.5, 7.0 Hz, 3H, Eta), 0.89 (t, J=7.3 Hz, 3H, 5-H);
13C NMR (CDCl3): δ175.3, 70.2, 61.4, 36.4, 17.9, 14.1, 13.6.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=1.0 mL/min): tR=15.0 min (1.4%), tR=17.5 min (98.6%);
IR (neat): 1745, 1496, 1454, 745, 701 cm−1;
1H NMR (CDCl3): δ7.33-7.17 (m, 10H, Ph), 5.08 (s, 1H, 2′-H), 4.98 (dd, J=7.0, 6.0 Hz, 1H, 2-H), 4.12 (dq, J=14.0, 7.5 Hz, 3H, Eta), 4.11 (dq, J=14.0, 7.0 Hz, 3H, Eta), 1.78-1.71 (m, 2H, 3-H), 1.32-1.28 (m, 2H, 4-H), 1.16 (dd, J=7.5, 7.0 Hz, 3H, Eta), 0.81 (t, J=7.5 Hz, 3H, 5-H);
13C NMR (CDCl3): δ172.1, 170.1, 138.4, 138.3, 128.7, 128.6, 128.4, 127.3, 127.2, 120.4, 72.9, 61.2, 56.8, 33.0, 18.3, 14.0, 13.5;
HR MS: calcd for C21H24O4Na (M+Na+) 363.1567. found 363.1569.
(Entry 30)
1H NMR (CDCl3): δ4.24 (q, J=7.0 Hz, 1H, 2-H), 3.72 (s, 3H, MeO), 3.16 (br s, 1H, OH), 1.36 (d, J=7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ176.0, 66.6, 52.3, 20.2.
HPLC (CHIRALCEL AD-H, i-PrOH/hexane=1/50, flow rate=0.75 mL/min): tR=16.4 min (98.3%), tR=19.7 min (1.7%);
IR (neat): 1744, 1496, 1454, 748, 699 cm−1;
1H NMR (CDCl3): δ7.28-7.20 (m, 8H, Ph), 7.19-7.13 (m, 2H, Ph), 5.07 (q, J=7.0 Hz, 1H, 2-H), 5.03 (s, 1H, 2′-H), 3.60 (s, 3H, MeO), 1.37 (d, J=7.0 Hz, 3H, 3-H);
13C NMR (CDCl3): δ171.9, 170.9, 138.3, 138.2, 128.7, 128.63, 128.55, 128.4, 127.3, 127.2, 69.2, 56.6, 52.2, 16.8;
HR MS: calcd for C18H18O4Na (M+Na+) 321.1097. found 321.1091.
As shown in the above reaction scheme, to a solvent (0.2 M) containing 0.6 equivalents of pivalic acid anhydride and 0.5 equivalents of diphenylacetic acid were added to 1.2 equivalents of diisopropyl ethylamine, 5% by mole of (+)-benzotetramisole (BTM), and a solvent containing 1 equivalent of racemic benzyl 2-hydroxy-3-methylbutanoate at room temperature in this order, and this reaction mixture was stirred at room temperature for 12 hrs. Thereafter, the reaction was stopped with a saturated aqueous sodium bicarbonate solution. After the organic layer was fractionated, the aqueous layer was extracted with diethyl ether three to five times. After the organic layer was mixed, the mixture was dried over anhydrous sodium sulfate. The solution was filtered and thereafter vacuum concentrated. Thus obtained mixture was fractionated on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a corresponding diester and unreacted optically active benzyl 2-hydroxy-3-methylbutanoate. The results are shown in Table 6.
| TABLE 6 | ||||||
| Yield [%] [a] | ee [%] | |||||
| No. | solvent | 6a; 6b | 6a; 6b | s | ||
| 31 | Et20 | 46; 50 | 92; 73 | 53 | ||
| 32 | i-Pr20 | 44; 54 | 92; 77 | 57 | ||
| 33 | MTBE [b] | 40; 54 | 93; 69 | 52 | ||
| 34 | CPME [c] | 36; 58 | 93; 53 | 50 | ||
| 35 | THF [d] | 38; 61 | 90; 57 | 33 | ||
| 36 | DMF [e] | 10; 82 | 92; 22 | 28 | ||
| [a] Isolation yield | ||||||
| [b] methyl tert-butyl ether | ||||||
| [c] cyclopentyl methyl ether | ||||||
| [d] tetrahydrofuran | ||||||
| [e] N,N-dimethylformamide | ||||||
As is seen from Table 6, all cases of Entries 31 to 36 exhibited favorable enantiomeric excess ee and reaction velocity ratio s for any of the solvents used, and in particular, the reaction velocity ratio s was as high as no less than 50 when the linear ether type solvent was used (Entries 31 to 34).
Benzyl (S)-14-(tert-butyldimethylsiloxy)-2-hydroxytetradecanoate obtained in Entry 26 of the aforementioned Test Example 3 is useful as, for example, an intermediate compound for producing 2-hydroxy-24-oxooctacosanolide that is an insect repellent. Accordingly, one example of the production method is shown in the following.
(Step 1)
To a solution of benzyl (S)-14-(tert-butyldimethylsiloxy)-2-hydroxytetradecanoate (46.5 mg, 0.100 mmol) in methylene chloride (0.5 mL) were added a solution of 4-methoxybenzyl 2,2,2-trichloroacetimidate (62.2 mg, 0.220 mmol) in methylene chloride (0.5 mL), and (±)-camphor sulfonic acid (2.3 mg, 0.010 mmol), and the mixture was stirred at room temperature for 16 hrs. The reaction system was diluted in hexane, filtered through Celite, and vacuum concentrated to obtain a crude product. Thus obtained crude product was purified on thin layer chromatography (developing solvent: benzene) to afford a compound A (19.5 mg, 33%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
IR (neat): 1749, 1613, 1514, 835, 775 cm−1;
1H NMR (CDCl3): δ7.39-7.31 (m, 5H, Ph), 7.23 (dt, J=8.5, 2.5 Hz, 2H, PMP), 6.85 (dt, J=8.5, 2.5 Hz, 2H, PMP), 5.21 (d, J=12.3 Hz, 1H, Bn), 5.16 (d, J=12.3 Hz, 1H, Bn), 4.61 (d, J=11.3 Hz, 1H, PMB), 4.33 (d, J=11.3 Hz, 1H, PMB), 3.94 (dd, J=7.0, 6.5 Hz, 1H, 2-H), 3.80 (s, 3H, OMe), 3.60 (t, J=6.8 Hz, 2H, 14-H), 1.77-1.69 (m, 2H, 3-H), 1.51 (tt, J=7.0, 7.0 Hz, 2H, 13-H), 1.42-1.17 (m, 18H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H), 0.90 (s, 9H, TBS), 0.05 (s, 6H, TBS);
13C NMR (CDCl3): δ173.0, 159.3, 135.7, 129.7, 129.63, 129.56, 128.32, 128.30, 113.7, 77.7, 71.9, 66.4, 63.3, 55.2, 33.0, 32.9, 29.65, 29.60, 29.60, 29.54, 29.46, 29.42, 29.2, 26.0, 25.8, 25.2, 18.4, −5.26;
HR MS: calcd for C35H56O5SiNa (M+Na+) 607.3789. found 607.3789.
(Step 2)
A solution of the compound A (19.5 mg, 33.3 μmol) in methylene chloride (0.67 mL) was cooled to 0° C., and thereto was added hydrogenated diisobutyl aluminum (1.0 M hexane solution, 0.10 mL, 0.100 mmol). The mixture was stirred for 5 min. To the reaction system was added a saturated aqueous potassium sodium tartrate solution to stop the reaction. The mixture was subjected to liquid separation by adding methylene chloride, and extraction from the aqueous layer was repeated three times with methylene chloride. The extracted layer was filtrated, and vacuum concentrated to give a crude product. Thus obtained crude product was purified on thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a compound B (12.9 mg, 81%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
IR (neat): 3438, 1613, 1514, 1100, 836, 775 cm−1;
1H NMR (CDCl3): δ7.27 (dt, J=8.5, 2.0 Hz, 2H, PMP), 6.88 (dt, J=8.5, 2.0 Hz, 2H, PMP), 4.56 (d, J=11.3 Hz, 1H, PMB), 4.46 (d, J=11.3 Hz, 1H, PMB), 3.80 (s, 3H, OMe), 3.69-3.65 (m, 1H, 2-H), 3.60 (t, J=6.5 Hz, 2H, 14H), 3.53-3.46 (m, 2H, 1-H), 1.65-1.43 (m, 4H, 3-H, 13-H), 1.37-1.24 (m, 19H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 11-H, 12-H, OH), 0.89 (s, 9H, TBS), 0.05 (s, 6H, TBS);
13C NMR (CDCl3): δ159.3, 130.6, 129.4, 113.9, 79.5, 71.2, 64.3, 63.3, 55.3, 32.9, 30.8, 29.8, 29.63, 29.62, 29.60, 29.60, 29.56, 29.4, 26.0, 25.8, 25.4, 18.4, −5.26;
HR MS: calcd for C28H52O4SiNa (M+Na+) 503.3527. found 503.3503.
(Step 3)
To a solution of the compound B (14.3 mg, 0.030 mmol) in N,N-dimethylformamide (0.15 mL) was added imidazole (8.1 mg, 0.119 mmol), and the reaction system was cooled to 0° C. Thereto was added tert-butyldiphenyl chlorosilane (15.3 μL), and the temperature of the reaction system was elevated to room temperature, followed by stirring the same for 15 min. To the reaction system was added a saturated aqueous ammonium chloride solution to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated three times with diethyl ether. Filtration, and vacuum concentration gave a crude product. Thus obtained crude product was purified on thin layer chromatography (developing solvent: hexane/ethyl acetate=5/1) to afford a compound C (19.0 mg, 89%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
[α]D 23=−14.5 (c 0.800, benzene);
IR (neat): 3071, 2928, 2855 cm−1;
1H NMR (CDCl3): δ7.70-7.67 (m, 4H, TBDPS), 7.45-7.34 (m, 6H, TBDPS), 7.23 (d, J=8.9 Hz, 2H, PMP), 6.85 (d, J=8.9 Hz, 2H, PMP), 4.60 (d, J=11.3 Hz, 1H, PMB), 4.44 (d, J=11.1 Hz, 1H, PMB), 3.80 (s, 3H, OMe), 3.73 (dd, J=10.5, 5.7 Hz, 1H, 1-H), 3.65-3.53 (m, 1H, 1-H), 3.60 (t, J=4.1 Hz, 2H, 14-H), 3.50-3.42 (m, 1H, 2-H), 1.56-1.48 (m, 5H), 1.39-1.12 (m, 17H), 1.06 (s, TBDPS, 9H), 0.90 (s, 9H, TBS), 0.05 (s, 6H, TBS);
13C NMR (CDCl3): δ160.9 (PMP), 135.6, 133.7, 131.0, 129.6, 129.3, 127.6, 113.7, 79.5, 71.8, 66.0, 63.4, 55.3, 32.9, 31.7, 29.6, 29.5, 26.8, 26.0, 25.8, 25.3, 19.5, 18.4, −5.3;
HR MS (FAB): calcd for C44H70O4Si2 (M+H+) 718.4813. found 718.4709.
(Step 4)
A solution of the compound C (6.07 g, 8.44 mmol) in tetrahydrofuran (168 mL) was cooled to 0° C., and thereto was added hydrochloric acid (1.0 M, 42.2 mL, 42.2 mmol). The temperature of the reaction system was elevated to room temperature, followed by stirring the same for 7 hrs. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium bicarbonate solution to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a compound D (4.88 g, 96%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
[α]D 23=−16.5 (c 1.00, benzene);
IR (neat): 3374 cm−1;
1H NMR (CDCl3): δ7.72-7.64 (m, 4H, TBDPS), 7.40-7.32 (m, 6H, TBDPS), 7.26-7.17 (m, 2H, PMP), 6.87-6.81 (m, 2H, PMP), 4.60 (d, J=11.3 Hz, 1H, PMB), 4.44 (d, J=11.1 Hz, 1H, PMB), 3.80 (s, 3H, OMe), 3.73 (dd, J=10.5, 5.9 Hz, 1H, 1-H), 3.68-3.60 (m, 3H, 1-H, 14-H), 3.53-3.43 (m, 1H, 2-H), 1.66-1.18 (m, 23H), 1.11 (s, 9H, TBDPS);
13C NMR (CDCl3): δ160.9, 135.6, 133.7, 131.0, 129.6, 129.3, 127.6, 113.7, 79.5, 71.8, 66.0, 63.1, 55.3, 32.8, 31.7, 29.7, 29.6, 29.4, 26.8, 25.7, 25.4, 19.4;
HR MS (FAB): calcd for C38H56O4Si (M+H+) 604.3948. found 604.3848.
(Step 5)
A solution of the compound D (3.34 g, 5.53 mmol) in benzene (27.5 mL) was cooled to 0° C., and thereto were added imidazole (941 mg, 13.8 mmol) and triphenylphosphine (3.63 g, 13.8 mmol). Thereafter, iodine (2.82 g, 11.1 mmol) was further added, the temperature of the reaction system was elevated to room temperature, followed by stirring the same for 30 min. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium sulfite solution to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=20/1) to afford a compound E (3.59 g, 91%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
[α]D 21=−6.61 (c 0.947, benzene);
IR (neat): 3070, 3048, 2998, 2927, 2854 cm−1;
1H NMR (CDCl3): δ7.71-7.63 (m, 4H, TBDPS), 7.46-7.33 (m, 6H, TBDPS), 7.26-7.23 (m, 2H, PMP), 6.88-6.84 (m, 2H, PMP), 4.61 (d, J=11.3 Hz, 1H, PMB), 4.44 (d, J=11.1 Hz, 1H, PMB), 3.80 (s, 3H, OMe), 3.73 (dd, J=10.5, 5.9 Hz, 1H, 1-H), 3.63 (dd, J=10.5, 4.6 Hz, 1H, 1-H), 3.53-3.43 (m, 1H, 2-H), 3.19 (t, J=7.0 Hz, 2H, 14-H), 1.82 (d, t, J=14.3, 7.0 Hz, 2H), 1.60-1.18 (m, 20H), 1.07 (s, 9H, TBS);
13C NMR (CDCl3): δ160.9, 135.6, 133.6, 131.2, 129.6, 129.3, 127.6, 113.6, 79.4, 71.8, 66.4, 55.3, 33.6, 31.6, 30.5, 29.7, 29.6, 29.4, 28.5, 26.8, 25.4, 19.2, 7.4;
HR MS (FAB): calcd for C38H55O3Si (M+H+) 714.2965. found 714.2864.
(Step 6)
To copper iodide (285 mg, 1.50 mmol) which had been dried beforehand by heating under a reduced pressure was added a solution of 2,2′-bipyridyl (235 mg, 1.50 mmol) in tetrahydrofuran (1.1 mL). Further, a solution of the compound E (3.57 g, 5.00 mmol) in tetrahydrofuran (10.0 mL) was added thereto. The reaction system was cooled to −17° C. and stirred for 15 min. Subsequently, a separately prepared Grignard reagent (0.555 M tetrahydrofuran solution, 18.4 mL, 10.2 mmol) was added thereto. The temperature of the reaction system was elevated to room temperature, followed by stirring the same for 1 hour. The reaction system was cooled to 0° C., and a saturated aqueous ammonium chloride solution was added thereto to stop the reaction. After diethyl ether was added, Celite was used to filtrate insoluble matter off. Liquid separation was carried out, and extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=40/1) to afford a compound F (4.10 g, 96%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
[α]D 21=−12.1 (c 1.01, benzene);
IR (neat): 3071, 3049, 2999, 2926, 2854 cm−1;
1H NMR (CDCl3): δ7.72-7.65 (m, 4H, TBDPS), 7.46-7.35 (m, 6H, TBDPS), 7.26-7.23 (m, 2H, PMP), 6.88-6.84 (m, 2H, PMP), 4.61 (d, J=11.3 Hz, 1H, PMB), 4.45 (d, J=11.3 Hz, 1H, PMB), 3.81 (s, 3H, OMe), 3.74 (dd, J=10.5, 5.9 Hz, 1H, 1-H), 3.63 (dd, J=10.5, 4.6 Hz, 1H, 1-H), 3.61 (t, J=6.8 Hz, 2H, 24-H), 3.54-3.43 (m, 1H, 2-H), 1.63-1.49 (m, 4H), 1.37-1.19 (m, 38H), 1.08 (s, 9H, TBDPS), 0.91 (s, 9H, TBS), 0.06 (s, 6H, TBS);
13C NMR (CDCl3): δ159.0, 135.6, 133.6, 131.2, 129.6, 129.3, 127.6, 113.6, 79.4, 71.8, 66.3, 63.3, 55.2, 32.8, 31.6, 29.7, 29.6, 29.4, 26.8, 26.0, 25.8, 25.4, 19.2, 18.4, −5.3;
HR MS (ESI TOF): calcd for C54H90O4Si2Na (M+Na+) 881.6270. found 881.6249.
(Step 7)
A solution of the compound F (1.65 g, 1.92 mmol) in tetrahydrofuran (96 mL) was cooled to 0° C., and thereto was added hydrochloric acid (1.0 M, 9.6 mL, 9.56 mmol). The temperature of the reaction system was elevated to room temperature, followed by stirring the same for 2.5 hrs. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium bicarbonate solution to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: benzene/ethyl acetate/methanol=30/1/1) to afford a compound G (1.34 g, 94%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
[α]D 27=−9.90 (c 1.03, benzene);
IR (neat): 3357 cm−1;
1H NMR (CDCl3): δ7.75-7.72 (m, 4H), 7.51-7.35 (m, 6H), 7.29-7.26 (m, 2H), 6.90-6.87 (m, 2H), 4.64 (d, J=11.3 Hz, 1H), 4.48 (d, J=11.3 Hz, 1H), 3.82 (s, 3H), 3.81-3.61 (m, 2H, 1-H), 3.65 (t, J=6.6 Hz, 2H, 24-H), 3.56-3.46 (m, 1H, 2-H), 1.65-1.18 (m, 42H), 1.11 (s, 9H);
13C NMR (CDCl3): δ159.0, 135.6, 133.6, 131.1, 129.6, 129.3, 127.6, 113.6, 79.4, 71.7, 66.3, 63.0, 55.2, 32.7, 31.6, 29.7, 29.6, 29.4, 26.8, 25.7, 25.3, 19.2;
HR MS (ESI TOF): calcd for C48H76O4SiNa (M+Na+) 767.5405. found 767.5406.
(Step 8)
To a solution of the compound G (3.08 g, 4.13 mmol) in methylene chloride (41.2 mL) was added pyridinium chlorochromate (1.34 g, 6.20 mmol), and the mixture was stirred for 11 hrs. The reaction system was diluted by adding diethyl ether. Gravity filtration, and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=10/1) to afford a compound H (2.52 g, 82%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
[α]D 22=−14.3 (c 1.03, benzene);
IR (neat): 1727 cm−1;
1H NMR (CDCl3): δ9.76 (s, 1H, CHO), 7.70-7.67 (m, 4H, TBDPS), 7.45-7.34 (m, 6H, TBDPS), 7.23 (d, J=8.7 Hz, 2H, PMP), 6.85 (d, J=9.0 Hz, 2H, PMP), 4.60 (d, J=11.4 Hz, 1H, PMB), 4.44 (d, J=11.4 Hz, 1H), 3.80 (s, 3H, PMB), 3.73 (dd, J=11.9, 5.9 Hz, 1H, 1-H), 3.62 (dd, J=10.8, 4.8 Hz, 1H, 1-H), 3.50-3.44 (m, 1H, 2-H), 2.42 (t, d, J=7.4, 1.8 Hz, 2H, 23-H), 1.65-1.44 (m, 4H, 3-H, 22-H), 1.35-1.18 (m, 38H, 4-H to 21-H), 1.06 (s, 9H, TBDPS);
13C NMR (CDCl3): δ203.0, 159.0, 135.6, 133.6, 131.2, 129.6, 129.3, 127.6, 113.6, 79.4, 71.7, 66.4, 55.2, 43.9, 31.6, 29.70, 29.63, 29.59, 29.41, 29.34, 29.14, 26.8, 25.4, 22.1, 19.2;
HR MS (ESI TOF): calcd for C48H74O4SiNa (M+Na+) 765.5249. found 765.5270.
(Step 9)
A solution of the compound H (2.52 g, 3.40 mmol) in tetrahydrofuran (7.6 mL) was cooled to 0° C., and a separately prepared Grignard reagent (0.686 M, 9.9 mL, 6.81 mmol) was added thereto, followed by stirring the mixture for 2 hrs. A saturated aqueous ammonium chloride solution was added to the reaction system to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1) to afford a compound I (2.70 g, 88%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
IR (neat): 3448 cm−1;
1H NMR (CDCl3): δ7.78-7.64 (m, 4H, TBDPS), 7.47-7.33 (m, 6H, TBDPS), 7.28-7.20 (m, 2H, PMP), 6.89-6.81 (m, 2H, PMP), 4.61 (d, J=11.1 Hz, 1H, PMB), 4.59 (s, 1H, THP), 4.45 (d, J=11.1 Hz, 1H, PMB), 3.93-3.36 (m, 8H, 1-H, 2-H, 24-H, 28-H, THP), 3.80 (s, 3H, OMe), 1.89-1.15 (m, 54H);
13C NMR (CDCl3): δ159.0, 135.6, 133.6, 131.2, 129.6, 129.3, 127.6, 113.6, 98.9, 79.4, 71.7, 67.5, 66.4, 64.3, 62.3, 55.2, 37.5, 37.1, 31.6, 30.7, 29.7, 29.6, 26.8, 25.6, 25.3, 22.3, 19.6, 19.2;
HR MS (ESI TOF): calcd for C57H92O6SiNa (M+Na+) 923.6555. found 923.6554.
(Step 10)
A solution of the compound I (1.38 g, 1.53 mmol) in methylene chloride (5 mL) was cooled to 0° C., and thereto were added dihydropyran (0.2 mL, 2.19 mmol) and p-toluenesulfonic acid monohydrate (32.7 mg, 0.190 mmol). The temperature of the reaction system was elevated to room temperature, followed by stirring the same for 2 hrs. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium bicarbonate solution to stop the reaction. Methylene chloride was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with methylene chloride. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=15/1) to afford a compound J (1.30 g, 86%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
IR (neat): 3070, 3044, 2924, 2853 cm−1;
1H NMR (CDCl3): δ7.71-7.67 (m, 4H, TBDPS), 7.47-7.35 (m, 6H, TBDPS), 7.26-7.17 (m, 2H, PMP), 6.88-6.80 (m, 2H, PMP), 4.60 (d, J=11.1 Hz, 1H, PMB), 4.58 (s, 1H, THP), 4.44 (d, J=11.3 Hz, 1H, PMB), 3.92-3.32 (m, 8H, 1-H, 2-H, 24-H, 28-H, THP), 3.80 (s, 3H, OMe), 1.88-1.11 (m, 54H), 1.07 (s, 9H, TBDPS);
13C NMR (CDCl3): δ158.9, 135.6, 133.6, 131.1, 129.6, 129.3, 127.6, 113.6, 100.5, 95.4, 79.4, 71.8, 67.5, 66.4, 62.7, 62.2, 62.1, 55.3, 35.0, 34.8, 30.8, 30.7, 29.9, 29.5, 26.8, 25.5, 25.0, 22.3, 20.0, 19.7, 19.6;
HR MS (ESI TOF): calcd for C62H100O7SiNa (M+Na+) 1007.7131. found 1007.7123.
(Step 11)
A solution of the compound J (654.6 mg, 0.664 mmol) in tetrahydrofuran (7.2 mL) was cooled to 0° C., and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.0 mL, 2.0 mmol) was added thereto. To the reaction system was added acetic acid (0.12 mL, 2.10 mmol), and the temperature was elevated to room temperature, followed by stirring the same for 22.5 hrs. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium bicarbonate solution to stop the reaction, Ethyl acetate was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with ethyl acetate. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a compound K (474 mg, 96%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
IR (neat): 3466 cm−1;
1H NMR (CDCl3): δ7.27 (d, J=8.4 Hz, 2H, PMP), 6.91-6.86 (m, 2H, PMP), 4.67-4.62 (m, 1H, THP), 4.60-4.55 (m, 1H, THP), 4.56 (d, J=11.3 Hz, 1H, PMB), 4.46 (d, J=11.1 Hz, 1H, PMB), 3.95-3.34 (m, 10H, 1-H, 2-H, 24-H, 28-H, THP), 3.81 (s, 3H, OMe), 1.86-1.38 (m, 20H, 3-H, 23-H, 25-H, 27-H, THP), 1.38-1.16 (m, 40H);
13C NMR (CDCl3): δ159.2, 130.6, 129.3, 113.8, 98.8, 97.6, 79.4, 71.1, 67.5, 64.3, 62.7, 62.3, 62.2, 55.3, 35.0, 34.8, 30.8, 30.7, 29.9, 29.5, 25.5, 25.0, 22.3, 20.0, 19.6;
HR MS (ESI TOF): calcd for C46H82O7Na (M+Na+) 769.5953. found 769.5953.
(Step 12)
To a solution of the compound K (588.1 mg, 0.787 mmol) in acetonitrile (3.9 mL) were added 2,2,6,6-tetramethylpiperidine 1-oxyl (18.0 mg, 0.115 mmol) and a buffered solution (2.95 mL). The temperature of the reaction system was elevated to an external temperature of 35° C., and an aqueous sodium hypochlorite solution (2.0 M, 1.58 mL, 3.15 mmol) and an aqueous sodium hypochlorite solution (5% NaOCl 0.1 mL/water 1.89 mL, 0.4 mL, 31.5 μmol) were added thereto. The reaction system was confirmed to be weekly acidic with a pH test paper, and stirred for 8.5 hrs. The temperature of the reaction system was elevated to room temperature, and water (5.9 mL) was added thereto. Thereafter, the reaction system was cooled to 0° C., and thereto was added a 6% aqueous sodium sulfite solution to stop the reaction. Diethyl ether was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with diethyl ether. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product of a compound L (599 mg, quant.) represented by the following formula. Thus obtained crude product was used in the next step without subjecting to purification.
It is to be noted that thus obtained crude product was purified on silica gel column chromatography (developing solvent: trichloromethane/methanol=10/1) to afford the compound L as a white solid, which was then analyzed by NMR. The physical properties were as in the following.
IR (neat): 3446, 1700 cm−1;
1H NMR (CDCl3): δ7.27 (d, J=8.7 Hz, 2H, PMP), 6.89 (d, J=8.7 Hz, 2H, PMP), 4.58 (s, 2H, THP), 4.55 (d, J=11.3 Hz, 1H, PMB), 4.47 (d, J=11.1 Hz, 1H, PMB), 3.93-3.34 (m, 8H, 2-H, 24-H, 28-H, THP), 3.80 (s, 3H, OMe), 1.95-1.16 (m, 60H);
HR MS (ESI TOF): calcd for C46H80O8Na (M+Na+) 783.5745. found 783.5739.
(Step 13)
A solution of the compound L (599 mg, 0.787 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C., and hydrochloric acid (1.0 M, 4.0 mL, 4.0 mmol) was added thereto. The temperature of the reaction system was elevated to room temperature, followed by stirring the same for 71 hrs. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium bicarbonate solution to stop the reaction. Ethyl acetate was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with ethyl acetate. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel column chromatography (developing solvent: dichloromethane/methanol=20/1) to afford a compound M (262 mg, 56%, 2 steps) represented by the following formula as a white solid. The physical properties were as in the following.
Mp: 62-63° C.;
IR (neat): 3416, 1716 cm−1;
1H NMR (CDCl3): δ7.29-7.26 (m, 2H, PMP), 6.92-6.87 (m, 2H, PMP), 4.60 (d, J=11.4 Hz, 1H, PMB), 4.46 (d, J=11.4 Hz, 1H, PMB), 3.98 (t, J=5.9 Hz, 1H, 2-H), 3.81 (s, 3H, OMe), 3.67 (t, J=6.3 Hz, 2H, 28-H), 3.61 (m, 1H, 24-H), 1.82-1.72 (m, 2H), 1.61-1.25 (m, 48H);
13C NMR (CDCl3): δ174.7, 159.3, 129.8, 129.0, 113.9, 72.3, 72.0, 70.0, 62.8, 55.3, 37.5, 36.9, 32.5, 32.3, 29.6, 29.4, 29.2, 25.6, 24.8, 21.8;
HR MS (ESI TOF): calcd for C36H64O6Na (M+Na+) 615.4595. found 615.4597.
(Step 14)
To a solution of 2-methyl-6-nitrobenzoic acid anhydride (24.8 mg, 72.0 μmol) in methylene chloride (9.6 mL) were added 4-dimethylaminopyridine N-oxide (1.7 mg, 12.3 μmol) and triethylamine (0.02 mL, 0.161 mmol), and the mixture was heated to reflux at an external temperature of 50° C. A solution of seco acid M (31.8 mg, 53.6 μmol) in tetrahydrofuran (16.3 mL) was added dropwise into the reaction system using a syringe pump over 12 hrs. After completing the dropwise addition, a solution of tetrahydrofuran (1.0 mL) was used for rinsing, and the mixture was stirred at 50° C. for 1 hour. The reaction system was cooled to 0° C., and thereto was added a saturated aqueous sodium bicarbonate solution to stop the reaction. Methylene chloride was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with methylene chloride. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford a compound N (23.6 mg, 77%) represented by the following formula as a colorless oily liquid. The physical properties were as in the following.
IR (neat): 3446, 1636 cm−1;
1H NMR (CDCl3): δ7.28 (d, J=8.5 Hz, 2H, PMP), 6.88 (d, J=8.5 Hz, 2H, PMP), 4.63 (d, J=11.0 Hz, 1H, PMB), 4.34 (d, J=11.0 Hz, 1H, PMB), 4.22-4.18 (m, 1H, 28-H), 4.16-4.09 (m, 1H, 28-H), 3.90 (t, J=6.5 Hz, 1H, 2-H), 3.80 (s, 3H, OMe), 3.66-3.55 (m, 1H, 24-H), 1.76-1.26 (m, 48H);
13C NMR (CDCl3): δ174.0, 159.3, 131.9, 129.7, 113.7, 77.4, 71.8, 71.6, 64.7, 55.3, 37.3, 36.8, 33.0, 29.35, 29.25, 29.17, 29.10, 29.03, 28.90, 28.86, 28.75, 28.66, 28.61, 28.56, 25.4, 25.3, 25.0, 22.1;
HR MS (ESI TOF): calcd for C36H62O5Na (M+Na+) 597.4489. found 597.4489.
(Step 15)
A solution of the compound N (60.1 mg, 0.105 mmol) in methylene chloride (1.0 mL) was added to molecular sieves 4 Å (62.7 mg) which had been heated beforehand to dry under a reduced pressure. Thereto was added N-methylmorpholine N-oxide (36.7 mg, 0.314 mmol), and the reaction system was cooled to 0° C. Tetrapropylammonium perruthenate (7.4 mg, 20.9 μmol) was added thereto, and the mixture was stirred for 4.5 hrs. After completing the reaction, filtration was carried out using silica gel (developing solvent: hexane/ethyl acetate=3/1), and vacuum concentration gave a crude product (59.9 mg, quant.) of a compound O represented by the following formula. Thus obtained crude product was used in the next step without subjecting to purification.
It is to be noted that thus obtained crude product was purified on silica gel thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to afford the compound O as a white solid, which was then analyzed by NMR. The physical properties were as in the following.
[α]D 22=−34.4 (c 0.753, benzene);
IR (neat): 1737, 1712 cm−1;
1H NMR (CDCl3): δ7.30-7.26 (m, 2H, PMP), 6.90-6.84 (m, 2H, PMP), 4.62 (d, J=11.1 Hz, 1H, PMB), 4.33 (d, J=11.3 Hz, 1H, PMB), 4.20-4.07 (m, 2H, 28-H), 3.89 (t, J=6.5 Hz, 1H, 2-H), 3.80 (s, 3H, OMe), 2.45 (t, J=7.0 Hz, 2H, 25-H), 2.38 (t, J=7.4 Hz, 2H, 23-H), 1.78-1.50 (m, 10H), 1.45-1.18 (m, 34H);
13C NMR (CDCl3): δ210.8, 173.0, 159.3, 132.7, 129.7, 113.3, 71.9, 64.4, 55.3, 42.8, 42.0, 33.0, 29.32, 29.23, 29.18, 29.09, 28.98, 28.78, 28.72, 28.64, 28.59, 28.2, 25.2, 23.8, 20.3;
HR MS (ESI TOF): calcd for C36H60O5Na (M+Na+) 595.4333, found 595.4333.
(Step 16)
To a solution of the compound O (59.9 mg, 0.105 mmol) in methylene chloride (2.0 mL) was added water (0.2 mL), and cooled to 0° C. Thereto was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (28.5 mg, 0.126 mmol), and the temperature of the reaction system was elevated to room temperature, followed by stirring the same for 38.5 hrs. The reaction system was cooled to 0° C., and thereto was added a buffered solution to stop the reaction. Methylene chloride was added and liquid separation was carried out. Extraction from the aqueous layer was repeated two times with methylene chloride. Organic layers were combined, and washed with water and saturated saline. After the mixture was dried over anhydrous sodium sulfate, filtration and vacuum concentration gave a crude product. Thus obtained crude product was purified on silica gel thin layer chromatography (developing solvent: benzene/diethyl ether=3/1) to afford 2-hydroxy-24-oxooctacosanolide intended (40.8 mg, 86%, 2 steps) represented by the following formula as a white solid. The physical properties were as in the following.
Mp: 67-68° C.;
[α]D 21=−9.6 (c 0.96, benzene);
IR (neat): 3445, 1739, 1713 cm−1;
1H NMR (CDCl3): δ4.28-4.24 (m, 1H, 28-H), 4.18-4.16 (m, 1H, 2-H), 4.13-4.09 (m, 1H, 28-H), 2.45 (t, J=7.0 Hz, 2H, 25-H), 2.40 (t, J=7.5 Hz, 2H, 23-H), 1.81-1.75 (m, 2H, 3-H), 1.69-1.63 (m, 2H, 27-H), 1.67-1.61 (m, 2H, 26-H), 1.61-1.56 (m, 2H, 22-H), 1.56-1.45 (m, 2H, 4-H), 1.45-1.17 (m, 34H, 5-H to 21-H);
13C NMR (CDCl3): δ210.7, 175.6, 70.4, 65.4, 42.8, 42.0, 34.4, 29.40, 29.29, 29.27, 29.20, 29.12, 28.98, 28.92, 28.89, 28.81, 28.74, 28.72, 28.67, 28.60, 28.58, 28.50, 28.1, 24.7, 23.7, 20.2;
HR MS (ESI TOF): calcd for C28H52O4Na (M+Na+) 475.3758. found 475.3758.
The optically active hydroxy ester obtained according to the production method of the present invention is useful also in producing an optically active amino alcohol. One example of the method for producing an optically active amino alcohol is shown below.
As shown in the above reaction scheme, ammonia gas was bubbled into a solution of benzyl (S)-lactate ester (45.2 mg, 0.251 mmol) in methanol (2.50 mL) at 0° C. for 70 min. After the reaction mixture was stirred at room temperature for 11 hrs, concentration gave a crude product of corresponding amide.
Subsequently, to a solution of thus obtained crude amide product in tetrahydrofuran (2.50 mL) was added lithium aluminium hydride (92.6 mg, 2.47 mmol) at 0° C. The reaction mixture was stirred at room temperature for 10 min, and the temperature was elevated to 55° C., followed by stirring the same for 18 hrs. Thereafter, water (200 μL) was added at 0° C. to stop the reaction. The reaction mixture was filtrated through Celite, and subjected to vacuum concentration. Thereafter, fractionation was carried out on silica gel thin layer chromatography (developing solvent: chloroform saturated with ammonia by aqueous ammonia extraction/methanol=50/1) to afford corresponding optically active amino alcohol (14.5 mg, 65%). The physical properties were as in the following.
[α]D 22=+44.4 (c 1.0, methanol);
1H NMR (CDCl3): δ3.65-2.55 (m, 1H), 3.80-2.40 (br m, 3H), 2.65 (dd, J=12.7, 2.7 Hz, 1H), 2.44 (dd, J=12.7, 8.1 Hz, 1H), 1.06 (d, J=6.3 Hz, 3H).
Claims (4)
1. A method for producing an optically active 2-hydroxy ester, the method comprising selectively esterifying one enantiomer of a racemic 2-hydroxy ester in a solvent containing a catalyst represented by any one of the following formulae (a) to (d), and a carboxylic acid anhydride, or a carboxylic acid anhydride and a carboxylic acid,
the racemic 2-hydroxy ester being a compound represented by formula (f) below,
the carboxylic acid anhydride being an anhydride of a carboxylic acid having a tertiary carbon atom or a quaternary carbon atom in the α-position, provided that the solvent contains a carboxylic acid anhydride but does not contain a carboxylic acid, whereas
the carboxylic acid has a tertiary carbon atom or a quaternary carbon atom in the α-position, provided that the solvent contains a carboxylic acid anhydride and a carboxylic acid,
wherein, X represents any one of the following substituents:
and R represents a protecting group,
wherein, Rf1 represents a monovalent organic group, and Rf2 represents a group selected from the group consisting of alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, and arylalkyl group.
2. The method for producing an optically active 2-hydroxy ester according to claim 1 , wherein the one enantiomer of the racemic 2-hydroxy ester is selectively esterified in a solvent comprising diphenylacetic acid anhydride as the carboxylic acid anhydride.
3. The method for producing an optically active 2-hydroxy ester according to claim 1 , wherein the one enantiomer of the racemic 2-hydroxy ester is selectively esterified in a solvent comprising pivalic acid anhydride as the carboxylic acid anhydride, and diphenylacetic acid as the carboxylic acid.
4. The method for producing an optically active 2-hydroxy ester according to claim 1 , wherein the solvent is a linear ether type solvent.
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| JP2009059850 | 2009-03-12 | ||
| JP2009-059850 | 2009-03-12 | ||
| JP2009-244060 | 2009-10-23 | ||
| JP2009244060 | 2009-10-23 | ||
| PCT/JP2010/053789 WO2010104034A1 (en) | 2009-03-12 | 2010-03-08 | Method for producing optically active 2-hydroxy ester and novel intermediate compound |
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| US8552215B2 true US8552215B2 (en) | 2013-10-08 |
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| US (1) | US8552215B2 (en) |
| EP (1) | EP2407447B1 (en) |
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| WO (1) | WO2010104034A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008140074A1 (en) | 2007-05-14 | 2008-11-20 | Tokyo University Of Science Educational Foundation Administrative Organization | Method for production of optically active carboxylic acid ester |
| WO2009113428A1 (en) | 2008-03-11 | 2009-09-17 | 学校法人東京理科大学 | Method for producing optically active ester and method for producing optically active carboxylic acid |
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| JP2898747B2 (en) * | 1989-12-27 | 1999-06-02 | 日東電工株式会社 | Method for producing optically active hydroxyester and method for producing and purifying optically active 5-membered lactone |
-
2010
- 2010-03-08 EP EP10750787.3A patent/EP2407447B1/en not_active Not-in-force
- 2010-03-08 US US13/255,465 patent/US8552215B2/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008140074A1 (en) | 2007-05-14 | 2008-11-20 | Tokyo University Of Science Educational Foundation Administrative Organization | Method for production of optically active carboxylic acid ester |
| WO2009113428A1 (en) | 2008-03-11 | 2009-09-17 | 学校法人東京理科大学 | Method for producing optically active ester and method for producing optically active carboxylic acid |
| US8115008B2 (en) * | 2008-03-11 | 2012-02-14 | Tokyo University Of Science Education Foundation Administrative Organization | Method for producing optically active ester and method for producing optically active carboxylic acid |
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| Publication number | Publication date |
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| WO2010104034A1 (en) | 2010-09-16 |
| EP2407447A1 (en) | 2012-01-18 |
| US20110319650A1 (en) | 2011-12-29 |
| JP5605716B2 (en) | 2014-10-15 |
| JPWO2010104034A1 (en) | 2012-09-13 |
| EP2407447A4 (en) | 2015-09-16 |
| EP2407447B1 (en) | 2018-04-18 |
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